Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mitochondrial Metabolism in Neoplastic Transformation
2.1. Mitochondria in PDAC Proliferation
2.2. Interaction with Stroma
2.3. Metastatic Dissemination
3. Metabolic and Molecular Subtypes of PDAC
4. Metabolic Alterations and Epigenetic Reprograming
5. Mechanism Underlying PDAC Progression via Metabolic Reprogramming
6. Mitochondrial Retrograde Signaling in PDAC
7. Mitochondria-Assisted ECM Dynamics in PDAC
8. Mitochondria in Immune Regulation
9. Targeting Mitochondrial Metabolism in PDAC
10. Antineoplastic Drug Resistance and Metabolism
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Padinharayil, H.; Varghese, J.; John, M.C.; Rajanikant, G.K.; Wilson, C.M.; Al-Yozbaki, M.; Renu, K.; Dewanjee, S.; Sanyal, R.; Dey, A.; et al. Non-Small Cell Lung Carcinoma (NSCLC): Implications on Molecular Pathology and Advances in Early Diagnostics and Therapeutics. Genes Dis. 2022. [Google Scholar] [CrossRef]
- Rahib, L.; Smith, B.D.; Aizenberg, R.; Rosenzweig, A.B.; Fleshman, J.M.; Matrisian, L.M. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res. 2014, 74, 2913–2921. [Google Scholar] [CrossRef] [PubMed]
- Ko, A.H. Progress in the Treatment of Metastatic Pancreatic Cancer and the Search for next Opportunities. J. Clin. Oncol. 2015, 33, 1779–1786. [Google Scholar] [CrossRef] [PubMed]
- Valle, S.; Alcalá, S.; Martin-Hijano, L.; Cabezas-Sáinz, P.; Navarro, D.; Muñoz, E.R.; Yuste, L.; Tiwary, K.; Walter, K.; Ruiz-Cañas, L.; et al. Exploiting Oxidative Phosphorylation to Promote the Stem and Immunoevasive Properties of Pancreatic Cancer Stem Cells. Nat. Commun. 2020, 11, 5265. [Google Scholar] [CrossRef]
- Smeitink, J.; van den Heuvel, L.; DiMauro, S. The Genetics and Pathology of Oxidative Phosphorylation. Nat. Rev. Genet. 2001, 2, 342–352. [Google Scholar] [CrossRef] [PubMed]
- Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does It Benefit Cancer Cells? Trends Biochem. Sci. 2016, 41, 211–218. [Google Scholar] [CrossRef]
- Liu, C.; Jin, Y.; Fan, Z. The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer. Front. Oncol. 2021, 11, 698023. [Google Scholar] [CrossRef]
- Vernucci, E.; Abrego, J.; Gunda, V.; Shukla, S.K.; Dasgupta, A.; Rai, V.; Chaika, N.; Buettner, K.; Illies, A.; Yu, F.; et al. Metabolic Alterations in Pancreatic Cancer Progression. Cancers 2019, 12, 2. [Google Scholar] [CrossRef]
- Rai, V.; Agrawal, S. Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2020, 21, 8502. [Google Scholar] [CrossRef]
- Suzuki, T.; Otsuka, M.; Seimiya, T.; Iwata, T.; Kishikawa, T.; Koike, K. The Biological Role of Metabolic Reprogramming in Pancreatic Cancer. MedComm 2020, 1, 302–310. [Google Scholar] [CrossRef]
- Martinez-Outschoorn, U.E.; Peiris-Pagés, M.; Pestell, R.G.; Sotgia, F.; Lisanti, M.P. Cancer Metabolism: A Therapeutic Perspective. Nat. Rev. Clin. Oncol. 2017, 14, 11–31. [Google Scholar] [CrossRef] [PubMed]
- Ying, H.; Kimmelman, A.C.; Lyssiotis, C.A.; Hua, S.; Chu, G.C.; Fletcher-Sananikone, E.; Locasale, J.W.; Son, J.; Zhang, H.; Coloff, J.L.; et al. Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell 2012, 149, 656–670. [Google Scholar] [CrossRef] [PubMed]
- Son, J.; Lyssiotis, C.A.; Ying, H.; Wang, X.; Hua, S.; Ligorio, M.; Perera, R.M.; Ferrone, C.R.; Mullarky, E.; Shyh-Chang, N.; et al. Glutamine Supports Pancreatic Cancer Growth through a KRAS-Regulated Metabolic Pathway. Nature 2013, 496, 101–105. [Google Scholar] [CrossRef] [PubMed]
- Qin, C.; Yang, G.; Yang, J.; Ren, B.; Wang, H.; Chen, G.; Zhao, F.; You, L.; Wang, W.; Zhao, Y. Metabolism of Pancreatic Cancer: Paving the Way to Better Anticancer Strategies. Mol. Cancer 2020, 19, 50. [Google Scholar] [CrossRef]
- Biancur, D.E.; Kimmelman, A.C. The Plasticity of Pancreatic Cancer Metabolism in Tumor Progression and Therapeutic Resistance. Biochim. Biophys. Acta Rev. Cancer 2018, 1870, 67–75. [Google Scholar] [CrossRef]
- Halbrook, C.J.; Lyssiotis, C.A. Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer. Cancer Cell 2017, 31, 5–19. [Google Scholar] [CrossRef]
- Garg, S.K.; Chari, S.T. Early Detection of Pancreatic Cancer. Curr. Opin. Gastroenterol. 2020, 36, 456–461. [Google Scholar] [CrossRef]
- Weinberg, F.; Hamanaka, R.; Wheaton, W.W.; Weinberg, S.; Joseph, J.; Lopez, M.; Kalyanaraman, B.; Mutlu, G.M.; Budinger, G.R.S.; Chandel, N.S. Mitochondrial Metabolism and ROS Generation Are Essential for Kras-Mediated Tumorigenicity. Proc. Natl. Acad. Sci. USA 2010, 107, 8788–8793. [Google Scholar] [CrossRef]
- Sabharwal, S.S.; Schumacker, P.T. Mitochondrial ROS in Cancer: Initiators, Amplifiers or an Achilles’ Heel? Nat. Rev. Cancer 2014, 14, 709–721. [Google Scholar] [CrossRef]
- Gaude, E.; Frezza, C. Defects in Mitochondrial Metabolism and Cancer. Cancer Metab. 2014, 2, 10. [Google Scholar] [CrossRef] [Green Version]
- Brandon, M.; Baldi, P.; Wallace, D.C. Mitochondrial Mutations in Cancer. Oncogene 2006, 25, 4647–4662. [Google Scholar] [CrossRef] [PubMed]
- Yuan, Y.; Ju, Y.S.; Kim, Y.; Li, J.; Wang, Y.; Yoon, C.J.; Yang, Y.; Martincorena, I.; Creighton, C.J.; Weinstein, J.N.; et al. Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers. Nat. Genet. 2020, 52, 342–352. [Google Scholar] [CrossRef] [PubMed]
- Galluzzi, L.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cecconi, F.; Choi, A.M.; Chu, C.T.; Codogno, P.; Colombo, M.I.; et al. Molecular Definitions of Autophagy and Related Processes. EMBO J. 2017, 36, 1811–1836. [Google Scholar] [PubMed]
- Park, S.M.; Ou, J.; Chamberlain, L.; Simone, T.M.; Yang, H.; Virbasius, C.M.; Ali, A.M.; Zhu, L.J.; Mukherjee, S.; Raza, A.; et al. U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-MRNA 3′ End Formation. Mol. Cell 2016, 62, 479–490. [Google Scholar] [CrossRef] [PubMed]
- Galluzzi, L.; Pietrocola, F.; Bravo-San Pedro, J.M.; Amaravadi, R.K.; Baehrecke, E.H.; Cecconi, F.; Codogno, P.; Debnath, J.; Gewirtz, D.A.; Karantza, V.; et al. Autophagy in Malignant Transformation and Cancer Progression. EMBO J. 2015, 34, 856–880. [Google Scholar] [CrossRef] [PubMed]
- Rosenfeldt, M.T.; O’Prey, J.; Morton, J.P.; Nixon, C.; Mackay, G.; Mrowinska, A.; Au, A.; Rai, T.S.; Zheng, L.; Ridgway, R.; et al. P53 Status Determines the Role of Autophagy in Pancreatic Tumour Development. Nature 2013, 504, 296–300. [Google Scholar] [CrossRef] [PubMed]
- Sumpter, R.; Sirasanagandla, S.; Fernández, Á.F.; Wei, Y.; Dong, X.; Franco, L.; Zou, Z.; Marchal, C.; Lee, M.Y.; Clapp, D.W.; et al. Fanconi Anemia Proteins Function in Mitophagy and Immunity. Cell 2016, 165, 867–881. [Google Scholar] [CrossRef]
- Liou, G.Y.; Döppler, H.; DelGiorno, K.E.; Zhang, L.; Leitges, M.; Crawford, H.C.; Murphy, M.P.; Storz, P. Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. Cell Rep. 2016, 14, 2325–2336. [Google Scholar] [CrossRef]
- Sullivan, L.B.; Gui, D.Y.; van der Heiden, M.G. Altered Metabolite Levels in Cancer: Implications for Tumour Biology and Cancer Therapy. Nat. Rev. Cancer 2016, 16, 680–693. [Google Scholar] [CrossRef]
- Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S.H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.T.; et al. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 2011, 19, 17–30. [Google Scholar] [CrossRef] [Green Version]
- Koivunen, P.; Lee, S.; Duncan, C.G.; Lopez, G.; Lu, G.; Ramkissoon, S.; Losman, J.A.; Joensuu, P.; Bergmann, U.; Gross, S.; et al. Transformation by the (R)-Enantiomer of 2-Hydroxyglutarate Linked to EGLN Activation. Nature 2012, 483, 484–488. [Google Scholar] [CrossRef]
- Kinch, L.; Grishin, N.V.; Brugarolas, J. Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2. Cancer Cell 2011, 20, 418–420. [Google Scholar] [CrossRef] [PubMed]
- Masgras, I.; Ciscato, F.; Brunati, A.M.; Tibaldi, E.; Indraccolo, S.; Curtarello, M.; Chiara, F.; Cannino, G.; Papaleo, E.; Lambrughi, M.; et al. Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. Cell Rep. 2017, 18, 659–672. [Google Scholar] [CrossRef] [PubMed]
- Sciacovelli, M.; Guzzo, G.; Morello, V.; Frezza, C.; Zheng, L.; Nannini, N.; Calabrese, F.; Laudiero, G.; Esposito, F.; Landriscina, M.; et al. The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase. Cell Metab. 2013, 17, 988–999. [Google Scholar] [CrossRef]
- Sandoval, I.T.; Delacruz, R.G.C.; Miller, B.N.; Hill, S.; Olson, K.A.; Gabriel, A.E.; Boyd, K.; Satterfield, C.; van Remmen, H.; Rutter, J.; et al. A Metabolic Switch Controls Intestinal Differentiation Downstream of Adenomatous Polyposis Coli (APC). eLife 2017, 6, e22706. [Google Scholar] [CrossRef]
- Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Control of Apoptosis by the BCL-2 Protein Family: Implications for Physiology and Therapy. Nat. Rev. Mol. Cell Biol. 2014, 15, 49–63. [Google Scholar] [CrossRef] [PubMed]
- Izzo, V.; Bravo-San Pedro, J.M.; Sica, V.; Kroemer, G.; Galluzzi, L. Mitochondrial Permeability Transition: New Findings and Persisting Uncertainties. Trends Cell Biol. 2016, 26, 655–667. [Google Scholar] [CrossRef] [PubMed]
- Serasinghe, M.N.; Wieder, S.Y.; Renault, T.T.; Elkholi, R.; Asciolla, J.J.; Yao, J.L.; Jabado, O.; Hoehn, K.; Kageyama, Y.; Sesaki, H.; et al. Mitochondrial Division Is Requisite to RAS-Induced Transformation and Targeted by Oncogenic MAPK Pathway Inhibitors. Mol. Cell 2015, 57, 521–536. [Google Scholar] [CrossRef]
- Kashatus, J.A.; Nascimento, A.; Myers, L.J.; Sher, A.; Byrne, F.L.; Hoehn, K.L.; Counter, C.M.; Kashatus, D.F. Erk2 Phosphorylation of Drp1 Promotes Mitochondrial Fission and MAPK-Driven Tumor Growth. Mol. Cell 2015, 57, 537–551. [Google Scholar] [CrossRef]
- Xie, Q.; Wu, Q.; Horbinski, C.M.; Flavahan, W.A.; Yang, K.; Zhou, W.; Dombrowski, S.M.; Huang, Z.; Fang, X.; Shi, Y.; et al. Mitochondrial Control by DRP1 in Brain Tumor Initiating Cells. Nat. Neurosci. 2015, 18, 501–510. [Google Scholar] [CrossRef] [Green Version]
- King, M.P.; Attardi, G. Human Cells Lacking MtDNA: Repopulation with Exogenous Mitochondria by Complementation. Science 1989, 246, 500–503. [Google Scholar] [CrossRef] [PubMed]
- Birsoy, K.; Wang, T.; Chen, W.W.; Freinkman, E.; Abu-Remaileh, M.; Sabatini, D.M. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell 2015, 162, 540–551. [Google Scholar] [CrossRef] [PubMed]
- Sullivan, L.B.; Gui, D.Y.; Hosios, A.M.; Bush, L.N.; Freinkman, E.; vander Heiden, M.G. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell 2015, 162, 552–563. [Google Scholar] [CrossRef]
- Pietrocola, F.; Galluzzi, L.; Bravo-San Pedro, J.M.; Madeo, F.; Kroemer, G. Acetyl Coenzyme A: A Central Metabolite and Second Messenger. Cell Metab. 2015, 21, 805–821. [Google Scholar] [CrossRef]
- Röhrig, F.; Schulze, A. The Multifaceted Roles of Fatty Acid Synthesis in Cancer. Nat. Rev. Cancer 2016, 16, 732–749. [Google Scholar] [CrossRef]
- Danhier, P.; Bański, P.; Payen, V.L.; Grasso, D.; Ippolito, L.; Sonveaux, P.; Porporato, P.E. Cancer Metabolism in Space and Time: Beyond the Warburg Effect. Biochim. Biophys. Acta Bioenerg. 2017, 1858, 556–572. [Google Scholar] [CrossRef] [PubMed]
- Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016, 23, 27–47. [Google Scholar] [CrossRef]
- Zhao, S.; Torres, A.; Henry, R.A.; Trefely, S.; Wallace, M.; Lee, J.V.; Carrer, A.; Sengupta, A.; Campbell, S.L.; Kuo, Y.-M.; et al. ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch. Cell Rep. 2016, 17, 1037–1052. [Google Scholar] [CrossRef]
- Metallo, C.M.; Gameiro, P.A.; Bell, E.L.; Mattaini, K.R.; Yang, J.; Hiller, K.; Jewell, C.M.; Johnson, Z.R.; Irvine, D.J.; Guarente, L.; et al. Reductive Glutamine Metabolism by IDH1 Mediates Lipogenesis under Hypoxia. Nature 2012, 481, 380–384. [Google Scholar] [CrossRef]
- Mullen, A.R.; Wheaton, W.W.; Jin, E.S.; Chen, P.H.; Sullivan, L.B.; Cheng, T.; Yang, Y.; Linehan, W.M.; Chandel, N.S.; Deberardinis, R.J. Reductive Carboxylation Supports Growth in Tumour Cells with Defective Mitochondria. Nature 2012, 481, 385–388. [Google Scholar] [CrossRef] [Green Version]
- Fan, J.; Ye, J.; Kamphorst, J.J.; Shlomi, T.; Thompson, C.B.; Rabinowitz, J.D. Corrigendum: Quantitative Flux Analysis Reveals Folate-Dependent NADPH Production. Nature 2014, 513, 574. [Google Scholar] [CrossRef]
- Ye, J.; Fan, J.; Venneti, S.; Wan, Y.W.; Pawel, B.R.; Zhang, J.; Finley, L.W.S.; Lu, C.; Lindsten, T.; Cross, J.R.; et al. Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia. Cancer Discov. 2014, 4, 1406–1417. [Google Scholar] [CrossRef] [PubMed]
- Coloff, J.L.; Murphy, J.P.; Braun, C.R.; Harris, I.S.; Shelton, L.M.; Kami, K.; Gygi, S.P.; Selfors, L.M.; Brugge, J.S. Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells. Cell Metab. 2016, 23, 867–880. [Google Scholar] [CrossRef] [PubMed]
- Dey, P.; Baddour, J.; Muller, F.; Wu, C.C.; Wang, H.; Liao, W.-T.; Lan, Z.; Chen, A.; Gutschner, T.; Kang, Y.; et al. Genomic Deletion of Malic Enzyme 2 Confers Collateral Lethality in Pancreatic Cancer. Nature 2017, 542, 119–123. [Google Scholar] [CrossRef]
- Hosein, A.N.; Brekken, R.A.; Maitra, A. Pancreatic Cancer Stroma: An Update on Therapeutic Targeting Strategies. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 487–505. [Google Scholar] [CrossRef]
- Olivares, O.; Mayers, J.R.; Gouirand, V.; Torrence, M.E.; Gicquel, T.; Borge, L.; Lac, S.; Roques, J.; Lavaut, M.N.; Berthezène, P.; et al. Collagen-Derived Proline Promotes Pancreatic Ductal Adenocarcinoma Cell Survival under Nutrient Limited Conditions. Nat. Commun. 2017, 8, 16031. [Google Scholar] [CrossRef]
- Hensley, C.T.; Faubert, B.; Yuan, Q.; Lev-Cohain, N.; Jin, E.; Kim, J.; Jiang, L.; Ko, B.; Skelton, R.; Loudat, L.; et al. Metabolic Heterogeneity in Human Lung Tumors. Cell 2016, 164, 681–694. [Google Scholar] [CrossRef]
- Kiberstis, P.A. It Takes a Village. Science 2019, 363, 1164–1165. [Google Scholar] [CrossRef]
- McGranahan, N.; Swanton, C. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell 2017, 168, 613–628. [Google Scholar] [CrossRef]
- Mayers, J.R.; Torrence, M.E.; Danai, L.V.; Papagiannakopoulos, T.; Davidson, S.M.; Bauer, M.R.; Lau, A.N.; Ji, B.W.; Dixit, P.D.; Hosios, A.M.; et al. Tissue of Origin Dictates Branched-Chain Amino Acid Metabolism in Mutant Kras-Driven Cancers. Science 2016, 353, 1161–1165. [Google Scholar] [CrossRef] [Green Version]
- Yuneva, M.O.; Fan, T.W.M.; Allen, T.D.; Higashi, R.M.; Ferraris, D.V.; Tsukamoto, T.; Matés, J.M.; Alonso, F.J.; Wang, C.; Seo, Y.; et al. The Metabolic Profile of Tumors Depends on Both the Responsible Genetic Lesion and Tissue Type. Cell Metab. 2012, 15, 157–170. [Google Scholar] [CrossRef] [PubMed]
- Davidson, S.M.; Papagiannakopoulos, T.; Olenchock, B.A.; Heyman, J.E.; Keibler, M.A.; Luengo, A.; Bauer, M.R.; Jha, A.K.; O’Brien, J.P.; Pierce, K.A.; et al. Environment Impacts the Metabolic Dependencies Article Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab. 2016, 23, 517–528. [Google Scholar] [CrossRef] [PubMed]
- Peitzsch, C.; Tyutyunnykova, A.; Pantel, K.; Dubrovska, A. Cancer Stem Cells: The Root of Tumor Recurrence and Metastases. In Seminars in Cancer Biology; Academic Press: Cambridge, MA, USA, 2017; Volume 44, pp. 10–24. [Google Scholar]
- Sousa, C.M.; Biancur, D.E.; Wang, X.; Halbrook, C.J.; Sherman, M.H.; Zhang, L.; Kremer, D.; Hwang, R.F.; Witkiewicz, A.K.; Ying, H.; et al. Pancreatic Stellate Cells Support Tumour Metabolism through Autophagic Alanine Secretion. Nature 2016, 536, 479–483. [Google Scholar] [CrossRef] [PubMed]
- Commisso, C.; Davidson, S.M.; Soydaner-Azeloglu, R.G.; Parker, S.J.; Kamphorst, J.J.; Hackett, S.; Grabocka, E.; Nofal, M.; Drebin, J.A.; Thompson, C.B.; et al. Macropinocytosis of Protein Is an Amino Acid Supply Route in Ras-Transformed Cells. Nature 2013, 497, 633–637. [Google Scholar] [CrossRef] [PubMed]
- Chang, C.H.; Qiu, J.; O’Sullivan, D.; Buck, M.D.; Noguchi, T.; Curtis, J.D.; Chen, Q.; Gindin, M.; Gubin, M.M.; van der Windt, G.J.W.; et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 2015, 162, 1229–1241. [Google Scholar] [CrossRef]
- Ho, P.C.; Bihuniak, J.D.; MacIntyre, A.N.; Staron, M.; Liu, X.; Amezquita, R.; Tsui, Y.C.; Cui, G.; Micevic, G.; Perales, J.C.; et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-Tumor T Cell Responses. Cell 2015, 162, 1217–1228. [Google Scholar] [CrossRef]
- Uyttenhove, C.; Pilotte, L.; Théate, I.; Stroobant, V.; Colau, D.; Parmentier, N.; Boon, T.; van den Eynde, B.J. Evidence for a Tumoral Immune Resistance Mechanism Based on Tryptophan Degradation by Indoleamine 2,3-Dioxygenase. Nat. Med. 2003, 9, 1269–1274. [Google Scholar] [CrossRef]
- Carmona-Carmona, C.A.; Pozza, E.D.; Ambrosini, G.; Errico, A.; Dando, I. Divergent Roles of Mitochondria Dynamics in Pancreatic Ductal Adenocarcinoma. Cancers 2022, 14, 2155. [Google Scholar] [CrossRef]
- Masugi, Y. The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities. Cancers 2022, 14, 3293. [Google Scholar] [CrossRef]
- López-Soto, A.; Gonzalez, S.; Smyth, M.J.; Galluzzi, L. Control of Metastasis by NK Cells. Cancer Cell 2017, 32, 135–154. [Google Scholar] [CrossRef]
- Moon, D.H.; Maddahi, J.; Silverman, D.H.S.; Glaspy, J.A.; Phelps, M.E.; Hoh, C.K. Accuracy of Whole-Body Fluorine-18-FDG PET for the Detection of Recurrent or Metastatic Breast Carcinoma. J. Nucl. Med. 1998, 39, 431–435. [Google Scholar] [PubMed]
- Frezza, C. Mitochondrial Metabolites: Undercover Signalling Molecules. Interface Focus 2017, 7, 20160100. [Google Scholar] [CrossRef] [PubMed]
- Sciacovelli, M.; Gonçalves, E.; Johnson, T.I.; Zecchini, V.R.; Da Costa, A.S.H.; Gaude, E.; Drubbel, A.V.; Theobald, S.J.; Abbo, S.R.; Tran, M.G.B.; et al. Fumarate Is an Epigenetic Modifier That Elicits Epithelial-to-Mesenchymal Transition. Nature 2016, 537, 544–547. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Li, Y.; Li, Z.; Lin, S.; Wang, H.; Sun, J.; Lan, C.; Wu, L.; Sun, D.; Huang, C.; et al. Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer. Cancer Res. 2022, 82, 2254–2268. [Google Scholar] [CrossRef]
- Espiau-Romera, P.; Courtois, S.; Parejo-Alonso, B.; Sancho, P. Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification. J. Clin. Med. 2020, 9, 4128. [Google Scholar] [CrossRef]
- Collisson, E.A.; Sadanandam, A.; Olson, P.; Gibb, W.J.; Truitt, M.; Gu, S.; Cooc, J.; Weinkle, J.; Kim, G.E.; Jakkula, L.; et al. Subtypes of Pancreatic Ductal Adenocarcinoma and Their Differing Responses to Therapy. Nat. Med. 2011, 17, 500–503. [Google Scholar] [CrossRef]
- Veenstra, V.L.; Garcia-Garijo, A.; van Laarhoven, H.W.; Bijlsma, M.F. Extracellular Influences: Molecular Subclasses and the Microenvironment in Pancreatic Cancer. Cancers 2018, 10, 34. [Google Scholar] [CrossRef]
- Moffitt, R.A.; Marayati, R.; Flate, E.L.; Volmar, K.E.; Loeza, S.G.H.; Hoadley, K.A.; Rashid, N.U.; Williams, L.A.; Eaton, S.C.; Chung, A.H.; et al. Virtual Microdissection Identifies Distinct Tumor- and Stroma-Specific Subtypes of Pancreatic Ductal Adenocarcinoma. Nat. Genet. 2015, 47, 1168–1178. [Google Scholar] [CrossRef]
- Bailey, P.; Chang, D.K.; Nones, K.; Johns, A.L.; Patch, A.M.; Gingras, M.C.; Miller, D.K.; Christ, A.N.; Bruxner, T.J.C.; Quinn, M.C.; et al. Genomic Analyses Identify Molecular Subtypes of Pancreatic Cancer. Nature 2016, 531, 47–52. [Google Scholar] [CrossRef]
- Zhao, L.; Zhao, H.; Yan, H. Gene Expression Profiling of 1200 Pancreatic Ductal Adenocarcinoma Reveals Novel Subtypes. BMC Cancer 2018, 18, 603. [Google Scholar] [CrossRef]
- Bryant, K.L.; Mancias, J.D.; Kimmelman, A.C.; Der, C.J. KRAS: Feeding Pancreatic Cancer Proliferation. Trends Biochem. Sci. 2014, 39, 91–100. [Google Scholar] [CrossRef] [PubMed]
- Gabitova-Cornell, L.; Surumbayeva, A.; Peri, S.; Franco-Barraza, J.; Restifo, D.; Weitz, N.; Ogier, C.; Goldman, A.R.; Hartman, T.R.; Francescone, R.; et al. Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell 2020, 38, 567–583.e11. [Google Scholar] [CrossRef] [PubMed]
- Karasinska, J.M.; Topham, J.T.; Kalloger, S.E.; Jang, G.H.; Denroche, R.E.; Culibrk, L.; Williamson, L.M.; Wong, H.L.; Lee, M.K.C.; O’Kane, G.M.; et al. Altered Gene Expression along the Glycolysis–Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer. Clin. Cancer Res. 2020, 26, 135–146. [Google Scholar] [CrossRef] [PubMed]
- Sun, L.; Zhang, H.; Gao, P. Metabolic Reprogramming and Epigenetic Modifications on the Path to Cancer. Protein Cell 2022, 13, 877–919. [Google Scholar] [CrossRef] [PubMed]
- Wong, C.C.; Qian, Y.; Yu, J. Interplay between Epigenetics and Metabolism in Oncogenesis: Mechanisms and Therapeutic Approaches. Oncogene 2017, 36, 3359–3374. [Google Scholar] [CrossRef] [PubMed]
- Zheng, Q.; Maksimovic, I.; Upad, A.; David, Y. Non-Enzymatic Covalent Modifications: A New Link between Metabolism and Epigenetics. Protein Cell 2020, 11, 401–416. [Google Scholar] [CrossRef] [PubMed]
- Li, S.T.; Huang, D.; Shen, S.; Cai, Y.; Xing, S.; Wu, G.; Jiang, Z.; Hao, Y.; Yuan, M.; Wang, N.; et al. Myc-Mediated SDHA Acetylation Triggers Epigenetic Regulation of Gene Expression and Tumorigenesis. Nat. Metab. 2020, 2, 256–269. [Google Scholar] [CrossRef]
- McDonald, O.G.; Li, X.; Saunders, T.; Tryggvadottir, R.; Mentch, S.J.; Warmoes, M.O.; Word, A.E.; Carrer, A.; Salz, T.H.; Natsume, S.; et al. Epigenomic Reprogramming during Pancreatic Cancer Progression Links Anabolic Glucose Metabolism to Distant Metastasis. Nat. Genet. 2017, 49, 367–376. [Google Scholar] [CrossRef]
- Yuan, H.; Han, Y.; Wang, X.; Li, N.; Liu, Q.; Yin, Y.; Wang, H.; Pan, L.; Li, L.; Song, K.; et al. SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways. Cancer Cell 2020, 38, 350–365.e7. [Google Scholar] [CrossRef]
- Bender, S.; Tang, Y.; Lindroth, A.M.; Hovestadt, V.; Jones, D.T.W.; Kool, M.; Zapatka, M.; Northcott, P.A.; Sturm, D.; Wang, W.; et al. Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. Cancer Cell 2013, 24, 660–672. [Google Scholar] [CrossRef] [Green Version]
- Kumari, R.; Deshmukh, R.S.; Das, S. Caspase-10 Inhibits ATP-Citrate Lyase-Mediated Metabolic and Epigenetic Reprogramming to Suppress Tumorigenesis. Nat. Commun. 2019, 10, 4255. [Google Scholar] [CrossRef] [PubMed]
- Lei, M.Z.; Li, X.X.; Zhang, Y.; Li, J.T.; Zhang, F.; Wang, Y.P.; Yin, M.; Qu, J.; Lei, Q.Y. Acetylation Promotes BCAT2 Degradation to Suppress BCAA Catabolism and Pancreatic Cancer Growth. Signal Transduct. Target. Ther. 2020, 5, 70. [Google Scholar] [CrossRef]
- Kottakis, F.; Nicolay, B.N.; Roumane, A.; Karnik, R.; Gu, H.; Nagle, J.M.; Boukhali, M.; Hayward, M.C.; Li, Y.Y.; Chen, T.; et al. LKB1 Loss Links Serine Metabolism to DNA Methylation and Tumorigenesis. Nature 2016, 539, 390–395. [Google Scholar] [CrossRef] [PubMed]
- Avolio, R.; Matassa, D.S.; Criscuolo, D.; Landriscina, M.; Esposito, F. Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer. Biomolecules 2020, 10, 135. [Google Scholar] [CrossRef]
- Wallace, D.C. Mitochondria and Cancer. Nat. Rev. Cancer 2012, 12, 685–698. [Google Scholar] [CrossRef]
- Chinnery, P.F.; Samuels, D.C.; Elson, J.; Turnbull, D.M. Accumulation of Mitochondrial DNA Mutations in Ageing, Cancer, and Mitochondrial Disease: Is There a Common Mechanism? Lancet 2002, 360, 1323–1325. [Google Scholar] [CrossRef] [PubMed]
- Gasparre, G.; Hervouet, E.; de Laplanche, E.; Demont, J.; Pennisi, L.F.; Colombel, M.; Mège-Lechevallier, F.; Scoazec, J.Y.; Bonora, E.; Smeets, R.; et al. Clonal Expansion of Mutated Mitochondrial DNA Is Associated with Tumor Formation and Complex I Deficiency in the Benign Renal Oncocytoma. Hum. Mol. Genet. 2008, 17, 986–995. [Google Scholar] [CrossRef] [PubMed]
- Salas, A.; Yao, Y.G.; Macaulay, V.; Vega, A.; Carracedo, Á.; Bandelt, H.J. A Critical Reassessment of the Role of Mitochondria in Tumorigenesis. PLoS Med. 2005, 2, e296. [Google Scholar] [CrossRef]
- Meierhofer, D.; Mayr, J.A.; Fink, K.; Schmeller, N.; Kofler, B.; Sperl, W. Mitochondrial DNA Mutations in Renal Cell Carcinomas Revealed No General Impact on Energy Metabolism. Br. J. Cancer 2006, 94, 268–274. [Google Scholar] [CrossRef]
- Czarnecka, A.M.; Czarnecki, J.S.; Kukwa, W.; Cappello, F.; Ścińska, A.; Kukwa, A. Molecular Oncology Focus—Is Carcinogenesis a “Mitochondriopathy”? J. Biomed. Sci. 2010, 17, 31. [Google Scholar] [CrossRef] [Green Version]
- Wallace, D.C. Bioenergetic Origins of Complexity and Disease. Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 1–16. [Google Scholar] [CrossRef] [PubMed]
- Parrella, P.; Xiao, Y.; Fliss, M.; Sanchez-Cespedes, M.; Mazzarelli, P.; Rinaldi, M.; Nicol, T.; Gabrielson, E.; Cuomo, C.; Cohen, D.; et al. Detection of Mitochondrial DNA Mutations in Primary Breast Cancer and Fine-Needle Aspirates. Cancer Res. 2001, 61, 7623–7626. [Google Scholar] [PubMed]
- Delpu, Y.; Hanoun, N.; Lulka, H.; Sicard, F.; Selves, J.; Buscail, L.; Torrisani, J.; Cordelier, P. Genetic and Epigenetic Alterations in Pancreatic Carcinogenesis. Curr. Genom. 2011, 12, 15–24. [Google Scholar] [CrossRef] [PubMed]
- CBioPortal for Cancer Genomics: MT-ND3, MT-CO1 and 2 Other Genes in Pancreatic Adenocarcinoma (TCGA, Firehose Legacy) and 5 Other Studies. Available online: https://www.cbioportal.org/results/mutations?cancer_study_list=paad_cptac_2021%2Cpaad_icgc%2Cpaad_qcmg_uq_2016%2Cpaad_tcga%2Cpaad_tcga_pan_can_atlas_2018%2Cpaad_utsw_2015&Z_SCORE_THRESHOLD=2.0&RPPA_SCORE_THRESHOLD=2.0&profileFilter=mutations%2Cstructural_variants%2Cgistic&case_set_id=all&gene_list=MT-ND3%252C%2520MT-CO1%252C%2520TFAM%252C%2520IDH2&geneset_list=%20&tab_index=tab_visualize&Action=Submit&mutations_gene=IDH2 (accessed on 8 January 2023).
- Lunt, S.Y.; vander Heiden, M.G. Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation. Annu. Rev. Cell Dev. Biol. 2011, 27, 441–464. [Google Scholar] [CrossRef]
- Zhang, C.; Liu, J.; Liang, Y.; Wu, R.; Zhao, Y.; Hong, X.; Lin, M.; Yu, H.; Liu, L.; Levine, A.J.; et al. Tumour-Associated Mutant p53 Drives TheWarburg Effect. Nat. Commun. 2013, 4, 2935. [Google Scholar] [CrossRef]
- Gaglio, D.; Metallo, C.M.; Gameiro, P.A.; Hiller, K.; Danna, L.S.; Balestrieri, C.; Alberghina, L.; Stephanopoulos, G.; Chiaradonna, F. Oncogenic K-Ras Decouples Glucose and Glutamine Metabolism to Support Cancer Cell Growth. Mol. Syst. Biol. 2011, 7, 523. [Google Scholar] [CrossRef]
- Chaika, N.V.; Gebregiworgis, T.; Lewallen, M.E.; Purohit, V.; Radhakrishnan, P.; Liu, X.; Zhang, B.; Mehla, K.; Brown, R.B.; Caffrey, T.; et al. MUC1 Mucin Stabilizes and Activates Hypoxia-Inducible Factor 1 Alpha to Regulate Metabolism in Pancreatic Cancer. Proc. Natl. Acad. Sci. USA 2012, 109, 13787–13792. [Google Scholar] [CrossRef]
- Baek, G.H.; Tse, Y.F.; Hu, Z.; Cox, D.; Buboltz, N.; McCue, P.; Yeo, C.J.; White, M.A.; DeBerardinis, R.J.; Knudsen, E.S.; et al. MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies. Cell Rep. 2014, 9, 2233–2249. [Google Scholar] [CrossRef]
- Shi, M.; Cui, J.; Du, J.; Wei, D.; Jia, Z.; Zhang, J.; Zhu, Z.; Gao, Y.; Xie, K. A Novel KLF4/LDHA Signaling Pathway Regulates Aerobic Glycolysis in and Progression of Pancreatic Cancer. Clin. Cancer Res. 2014, 20, 4370–4380. [Google Scholar] [CrossRef]
- Cui, J.; Shi, M.; Xie, D.; Wei, D.; Jia, Z.; Zheng, S.; Gao, Y.; Huang, S.; Xie, K. FOXM1 Promotes the Warburg Effect and Pancreatic Cancer Progression via Transactivation of LDHA Expression. Clin. Cancer Res. 2014, 20, 2595–2606. [Google Scholar] [CrossRef] [Green Version]
- Amendola, C.R.; Mahaffey, J.P.; Parker, S.J.; Ahearn, I.M.; Chen, W.-C.; Zhou, M.; Court, H.; Shi, J.; Mendoza, S.L.; Morten, M.J.; et al. KRAS4A Directly Regulates Hexokinase 1. Nature 2019, 576, 482–486. [Google Scholar] [CrossRef] [PubMed]
- Slawson, C.; Hart, G.W. O-GlcNAc Signalling: Implications for Cancer Cell Biology. Nat. Rev. Cancer 2011, 11, 678–684. [Google Scholar]
- Guillaumond, F.; Leca, J.; Olivares, O.; Lavaut, M.N.; Vidal, N.; Berthezène, P.; Dusetti, N.J.; Loncle, C.; Calvo, E.; Turrini, O.; et al. Strengthened Glycolysis under Hypoxia Supports Tumor Symbiosis and Hexosamine Biosynthesis in Pancreatic Adenocarcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, 3919–3924. [Google Scholar] [CrossRef] [PubMed]
- Santana-Codina, N.; Roeth, A.A.; Zhang, Y.; Yang, A.; Mashadova, O.; Asara, J.M.; Wang, X.; Bronson, R.T.; Lyssiotis, C.A.; Ying, H.; et al. Oncogenic KRAS Supports Pancreatic Cancer through Regulation of Nucleotide Synthesis. Nat. Commun. 2018, 9, 4945. [Google Scholar] [CrossRef] [PubMed]
- Gunda, V.; Souchek, J.; Abrego, J.; Shukla, S.K.; Goode, G.D.; Vernucci, E.; Dasgupta, A.; Chaika, N.V.; King, R.J.; Li, S.; et al. MUC1-Mediated Metabolic Alterations Regulate Response to Radiotherapy in Pancreatic Cancer. Clin. Cancer Res. 2017, 23, 5881–5891. [Google Scholar] [CrossRef]
- Shukla, S.K.; Purohit, V.; Mehla, K.; Gunda, V.; Chaika, N.V.; Vernucci, E.; King, R.J.; Abrego, J.; Goode, G.D.; Dasgupta, A.; et al. MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell 2017, 32, 71–87. [Google Scholar] [CrossRef]
- Gebregiworgis, T.; Purohit, V.; Shukla, S.K.; Tadros, S.; Chaika, N.V.; Abrego, J.; Mulder, S.E.; Gunda, V.; Singh, P.K.; Powers, R. Glucose Limitation Alters Glutamine Metabolism in MUC1-Overexpressing Pancreatic Cancer Cells. J. Proteome Res. 2017, 16, 3536–3546. [Google Scholar] [CrossRef]
- Olou, A.A.; King, R.J.; Yu, F.; Singh, P.K. MUC1 Oncoprotein Mitigates ER Stress via CDA-Mediated Reprogramming of Pyrimidine Metabolism. Oncogene 2020, 39, 3381–3395. [Google Scholar] [CrossRef]
- Kerk, S.A.; Papagiannakopoulos, T.; Shah, Y.M.; Lyssiotis, C.A. Metabolic Networks in Mutant KRAS-Driven Tumours: Tissue Specificities and the Microenvironment. Nat. Rev. Cancer 2021, 21, 510–525. [Google Scholar] [CrossRef]
- Kaira, K.; Sunose, Y.; Arakawa, K.; Ogawa, T.; Sunaga, N.; Shimizu, K.; Tominaga, H.; Oriuchi, N.; Itoh, H.; Nagamori, S.; et al. Prognostic Significance of L-Type Amino-Acid Transporter 1 Expression in Surgically Resected Pancreatic Cancer. Br. J. Cancer 2012, 107, 632–638. [Google Scholar] [CrossRef]
- Coothankandaswamy, V.; Cao, S.; Xu, Y.; Prasad, P.D.; Singh, P.K.; Reynolds, C.P.; Yang, S.; Ogura, J.; Ganapathy, V.; Bhutia, Y.D. Amino Acid Transporter SLC6A14 Is a Novel and Effective Drug Target for Pancreatic Cancer. Br. J. Pharmacol. 2016, 173, 3292–3306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hensley, C.T.; Wasti, A.T.; DeBerardinis, R.J. Glutamine and Cancer: Cell Biology, Physiology, and Clinical Opportunities. J. Clin. Investig. 2013, 123, 3678–3684. [Google Scholar] [CrossRef]
- Deberardinis, R.J.; Cheng, T. Q’s next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer. Oncogene 2010, 29, 313–324. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Pavlova, N.N.; Thompson, C.B. Cancer Cell Metabolism: The Essential Role of the Nonessential Amino Acid, Glutamine. EMBO J. 2017, 36, 1302–1315. [Google Scholar] [CrossRef] [PubMed]
- Altman, B.J.; Stine, Z.E.; Dang, C.V. From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy. Nat. Rev. Cancer 2016, 16, 619–634. [Google Scholar] [CrossRef] [PubMed]
- Abrego, J.; Gunda, V.; Vernucci, E.; Shukla, S.K.; King, R.J.; Dasgupta, A.; Goode, G.; Murthy, D.; Yu, F.; Singh, P.K. GOT1-Mediated Anaplerotic Glutamine Metabolism Regulates Chronic Acidosis Stress in Pancreatic Cancer Cells. Cancer Lett. 2017, 400, 37–46. [Google Scholar] [CrossRef]
- Morris, J.P.; Yashinskie, J.J.; Koche, R.; Chandwani, R.; Tian, S.; Chen, C.C.; Baslan, T.; Marinkovic, Z.S.; Sánchez-Rivera, F.J.; Leach, S.D.; et al. Alpha-Ketoglutarate Links p53 to Cell Fate during Tumour Suppression. Nature 2019, 573, 595–599. [Google Scholar] [CrossRef]
- Daher, B.; Parks, S.K.; Durivault, J.; Cormerais, Y.; Baidarjad, H.; Tambutte, E.; Pouysségur, J.; Vučetić, M. Genetic Ablation of the Cystine Transporter XCT in PDAC Cells Inhibits MTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses. Cancer Res. 2019, 79, 3877–3890. [Google Scholar] [CrossRef]
- Mayers, J.R.; Wu, C.; Clish, C.B.; Kraft, P.; Torrence, M.E.; Fiske, B.P.; Yuan, C.; Bao, Y.; Townsend, M.K.; Tworoger, S.S.; et al. Elevation of Circulating Branched-Chain Amino Acids Is an Early Event in Human Pancreatic Adenocarcinoma Development. Nat. Med. 2014, 20, 1193–1198. [Google Scholar] [CrossRef]
- Katagiri, R.; Goto, A.; Nakagawa, T.; Nishiumi, S.; Kobayashi, T.; Hidaka, A.; Budhathoki, S.; Yamaji, T.; Sawada, N.; Shimazu, T.; et al. Increased Levels of Branched-Chain Amino Acid Associated With Increased Risk of Pancreatic Cancer in a Prospective Case–Control Study of a Large Cohort. Gastroenterology 2018, 155, 1474–1482.e1. [Google Scholar] [CrossRef]
- Sunami, Y.; Rebelo, A.; Kleeff, J. Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells. Cancers 2018, 10, 3. [Google Scholar] [CrossRef] [Green Version]
- Swierczynski, J.; Hebanowska, A.; Sledzinski, T. Role of Abnormal Lipid Metabolism in Development, Progression, Diagnosis and Therapy of Pancreatic Cancer. World J. Gastroenterol. 2014, 20, 2279–2303. [Google Scholar] [CrossRef] [PubMed]
- Guillaumond, F.; Bidaut, G.; Ouaissi, M.; Servais, S.; Gouirand, V.; Olivares, O.; Lac, S.; Borge, L.; Roques, J.; Gayet, O.; et al. Cholesterol Uptake Disruption, in Association with Chemotherapy, Is a Promising Combined Metabolic Therapy for Pancreatic Adenocarcinoma. Proc. Natl. Acad. Sci. USA 2015, 112, 2473–2478. [Google Scholar] [CrossRef] [PubMed]
- Oni, T.E.; Biffi, G.; Baker, L.A.; Hao, Y.; Tonelli, C.; Somerville, T.D.; Deschênes, A.; Belleau, P.; Hwang, C.-I.; Sánchez-Rivera, F.J.; et al. SOAT1 Promotes Mevalonate Pathway Dependency in Pancreatic Cancer. J. Exp. Med. 2020, 217, e20192389. [Google Scholar] [CrossRef]
- Vikramdeo, K.S.; Anand, S.; Khan, M.A.; Khushman, M.; Heslin, M.J.; Singh, S.; Singh, A.P.; Dasgupta, S. Detection of Mitochondrial DNA Mutations in Circulating Mitochondria-Originated Extracellular Vesicles for Potential Diagnostic Applications in Pancreatic Adenocarcinoma. Sci. Rep. 2022, 12, 18455. [Google Scholar] [CrossRef]
- Sansone, P.; Savini, C.; Kurelac, I.; Chang, Q.; Amato, L.B.; Strillacci, A.; Stepanova, A.; Iommarini, L.; Mastroleo, C.; Daly, L.; et al. Packaging and Transfer of Mitochondrial DNA via Exosomes Regulate Escape from Dormancy in Hormonal Therapy-Resistant Breast Cancer. Proc. Natl. Acad. Sci. USA 2017, 114, E9066–E9075. [Google Scholar] [CrossRef]
- Ruivo, C.F.; Bastos, N.; Adem, B.; Batista, I.; Duraes, C.; Melo, C.A.; Castaldo, S.A.; Campos-Laborie, F.; Moutinho-Ribeiro, P.; Morão, B.; et al. Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to Fuel Tumour Progression. Gut 2022, 71, 2043–2068. [Google Scholar] [CrossRef]
- Patel, G.K.; Khan, M.A.; Bhardwaj, A.; Srivastava, S.K.; Zubair, H.; Patton, M.C.; Singh, S.; Khushman, M.; Singh, A.P. Exosomes Confer Chemoresistance to Pancreatic Cancer Cells by Promoting ROS Detoxification and MiR-155-Mediated Suppression of Key Gemcitabine-Metabolising Enzyme, DCK. Br. J. Cancer 2017, 116, 609–619. [Google Scholar] [CrossRef]
- Tang, P.; Tao, L.; Yuan, C.; Zhang, L.; Xiu, D. Serum Derived Exosomes from Pancreatic Cancer Patients Promoted Metastasis: An ITRAQ-Based Proteomic Analysis. OncoTargets Ther. 2019, 12, 9329–9339. [Google Scholar] [CrossRef]
- Amuthan, G.; Biswas, G.; Zhang, S.Y.; Klein-Szanto, A.; Vijayasarathy, C.; Avadhani, N.G. Mitochondria-to-Nucleus Stress Signaling Induces Phenotypic Changes, Tumor Progression and Cell Invasion. EMBO J. 2001, 20, 1910–1920. [Google Scholar] [CrossRef] [PubMed]
- Biswas, G.; Tang, W.; Sondheimer, N.; Guha, M.; Bansal, S.; Avadhani, N.G. A Distinctive Physiological Role for IκBβ in the Propagation of Mitochondrial Respiratory Stress Signaling. J. Biol. Chem. 2008, 283, 12586–12594. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guha, M.; Srinivasan, S.; Biswas, G.; Avadhani, N.G. Activation of a Novel Calcineurin-Mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress. J. Biol. Chem. 2007, 282, 14536–14546. [Google Scholar] [CrossRef] [PubMed]
- Guha, M.; Pan, H.; Fang, J.K.; Avadhani, N.G. Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress. Mol. Biol. Cell 2009, 20, 4107–4119. [Google Scholar] [CrossRef] [PubMed]
- Guha, M.; Fang, J.K.; Monks, R.; Birnbaum, M.J.; Avadhani, N.G. Activation of Akt Is Essential for the Propagation of Mitochondrial Respiratory Stress Signaling and Activation of the Transcriptional Coactivator Heterogeneous Ribonucleoprotein A2. Mol. Biol. Cell 2010, 21, 3578–3589. [Google Scholar] [CrossRef]
- Guha, M.; Tang, W.; Sondheimer, N.; Avadhani, N.G. Role of Calcineurin, HnRNPA2 and Akt in Mitochondrial Respiratory Stress-Mediated Transcription Activation of Nuclear Gene Targets. Biochim. Biophys. Acta Bioenerg. 2010, 1797, 1055–1065. [Google Scholar] [CrossRef]
- Cox, T.R. The Matrix in Cancer. Nat. Rev. Cancer 2021, 21, 217–238. [Google Scholar] [CrossRef]
- Kamphorst, J.J.; Nofal, M.; Commisso, C.; Hackett, S.R.; Lu, W.; Grabocka, E.; vander Heiden, M.G.; Miller, G.; Drebin, J.A.; Bar-Sagi, D.; et al. Human Pancreatic Cancer Tumors Are Nutrient Poor and Tumor Cells Actively Scavenge Extracellular Protein. Cancer Res. 2015, 75, 544–553. [Google Scholar] [CrossRef]
- Nazemi, M.; Rainero, E. Cross-Talk Between the Tumor Microenvironment, Extracellular Matrix, and Cell Metabolism in Cancer. Front. Oncol. 2020, 10, 239. [Google Scholar] [CrossRef]
- Romani, P.; Valcarcel-Jimenez, L.; Frezza, C.; Dupont, S. Crosstalk between Mechanotransduction and Metabolism. Nat. Rev. Mol. Cell Biol. 2021, 22, 22–38. [Google Scholar] [CrossRef]
- Li, J.; Huang, Q.; Long, X.; Guo, X.; Sun, X.; Jin, X.; Li, Z.; Ren, T.; Yuan, P.; Huang, X.; et al. Mitochondrial Elongation-Mediated Glucose Metabolism Reprogramming Is Essential for Tumour Cell Survival during Energy Stress. Oncogene 2017, 36, 4901–4912. [Google Scholar] [CrossRef]
- Papalazarou, V.; Zhang, T.; Paul, N.R.; Juin, A.; Cantini, M.; Maddocks, O.D.K.; Salmeron-Sanchez, M.; Machesky, L.M. The Creatine–Phosphagen System Is Mechanoresponsive in Pancreatic Adenocarcinoma and Fuels Invasion and Metastasis. Nat. Metab. 2020, 2, 62–80. [Google Scholar] [CrossRef] [PubMed]
- Buchheit, C.L.; Rayavarapu, R.R.; Schafer, Z.T. The Regulation of Cancer Cell Death and Metabolism by Extracellular Matrix Attachment. Semin. Cell Dev. Biol. 2012, 23, 402–411. [Google Scholar] [CrossRef] [PubMed]
- Gilmore, A.P.; Owens, T.W.; Foster, F.M.; Lindsay, J. How Adhesion Signals Reach a Mitochondrial Conclusion—ECM Regulation of Apoptosis. Curr. Opin. Cell Biol. 2009, 21, 654–661. [Google Scholar] [CrossRef] [PubMed]
- Vaquero, E.C.; Edderkaoui, M.; Nam, K.J.; Gukovsky, I.; Pandol, S.J.; Gukovskaya, A.S. Extracellular Matrix Proteins Protect Pancreatic Cancer Cells from Death via Mitochondrial and Nonmitochondrial Pathways. Gastroenterology 2003, 125, 1188–1202. [Google Scholar] [CrossRef] [PubMed]
- Hawk, M.A.; Gorsuch, C.L.; Fagan, P.; Lee, C.; Kim, S.E.; Hamann, J.C.; Mason, J.A.; Weigel, K.J.; Tsegaye, M.A.; Shen, L.; et al. RIPK1-Mediated Induction of Mitophagy Compromises the Viability of Extracellular-Matrix-Detached Cells. Nat. Cell Biol. 2018, 20, 272–284. [Google Scholar] [CrossRef]
- van Waveren, C.; Sun, Y.; Cheung, H.S.; Moraes, C.T. Oxidative Phosphorylation Dysfunction Modulates Expression of Extracellular Matrix—Remodeling Genes and Invasion. Carcinogenesis 2006, 27, 409–418. [Google Scholar] [CrossRef] [PubMed]
- Mills, E.L.; Kelly, B.; O’Neill, L.A.J. Mitochondria Are the Powerhouses of Immunity. Nat. Immunol. 2017, 18, 488–498. [Google Scholar] [CrossRef]
- Cherry, C.; Thompson, B.; Saptarshi, N.; Wu, J.; Hoh, J. 2016: A “Mitochondria” Odyssey. Trends Mol. Med. 2016, 22, 391–403. [Google Scholar] [CrossRef]
- Pearce, E.L.; Pearce, E.J. Metabolic Pathways in Immune Cell Activation and Quiescence. Immunity 2013, 38, 633–643. [Google Scholar] [CrossRef]
- Krawczyk, C.M.; Holowka, T.; Sun, J.; Blagih, J.; Amiel, E.; DeBerardinis, R.J.; Cross, J.R.; Jung, E.; Thompson, C.B.; Jones, R.G.; et al. Toll-like Receptor-Induced Changes in Glycolytic Metabolism Regulate Dendritic Cell Activation. Blood 2010, 115, 4742–4749. [Google Scholar] [CrossRef]
- Neill, O. Succinate Is an Inflammatory Signal That Induces IL-1 Beta NIH Public Access. Nature 2013, 496, 238–242. [Google Scholar]
- Everts, B.; Amiel, E.; van der Windt, G.J.W.; Freitas, T.C.; Chott, R.; Yarasheski, K.E.; Pearce, E.L.; Pearce, E.J. Commitment to Glycolysis Sustains Survival of NO-Producing Inflammatory Dendritic Cells. Blood 2012, 120, 1422–1431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beltrán, B.; Mathur, A.; Duchen, M.R.; Erusalimsky, J.D.; Moncada, S. The Effect of Nitric Oxide on Cell Respiration: A Key to Understanding Its Role in Cell Survival or Death. Proc. Natl. Acad. Sci. USA 2000, 97, 14602–14607. [Google Scholar] [CrossRef] [PubMed]
- Chandel, N.S.; Schumacker, P.T.; Arch, R.H. Reactive Oxygen Species Are Downstream Products of TRAF-Mediated Signal Transduction. J. Biol. Chem. 2001, 276, 42728–42736. [Google Scholar] [CrossRef]
- Kelly, B.; Tannahill, G.M.; Murphy, M.P.; O’Neill, L.A.J. Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1β (IL-1β) and Boosts Interleukin-10 (IL-10) in Lipopolysaccharide (LPS)-Activated Macrophages. J. Biol. Chem. 2015, 290, 20348–20359. [Google Scholar] [CrossRef]
- Colegio, O.R.; Chu, N.Q.; Szabo, A.L.; Chu, T.; Rhebergen, A.M.; Jairam, V.; Cyrus, N.; Brokowski, C.E.; Eisenbarth, S.C.; Phillips, G.M.; et al. Functional Polarization of Tumour-Associated Macrophages by Tumour-Derived Lactic Acid. Nature 2014, 513, 559–563. [Google Scholar] [CrossRef]
- Selleri, S.; Bifsha, P.; Civini, S.; Pacelli, C.; Dieng, M.M.; Lemieux, W.; Jin, P.; Bazin, R.; Patey, N.; Marincola, F.M.; et al. Human Mesenchymal Stromal Cell-Secreted Lactate Induces M2-Macrophage Differentiation by Metabolic Reprogramming. Oncotarget 2016, 7, 30193–30210. [Google Scholar] [CrossRef]
- Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef]
- Viale, A.; Pettazzoni, P.; Lyssiotis, C.A.; Ying, H.; Sánchez, N.; Marchesini, M.; Carugo, A.; Green, T.; Seth, S.; Giuliani, V.; et al. Oncogene Ablation-Resistant Pancreatic Cancer Cells Depend on Mitochondrial Function. Nature 2014, 514, 628–632. [Google Scholar] [CrossRef]
- Katajisto, P.; Döhla, J.; Chaffer, C.L.; Pentinmikko, N.; Marjanovic, N.; Iqbal, S.; Zoncu, R.; Chen, W.; Weinberg, R.A.; Sabatini, D.M. Asymmetric Apportioning of Aged Mitochondria between Daughter Cells Is Required for Stemness. Science 2015, 348, 340–343. [Google Scholar] [CrossRef]
- Lamb, R.; Ozsvari, B.; Lisanti, C.L.; Tanowitz, H.B.; Howell, A.; Martinez-Outschoorn, U.E.; Sotgia, F.; Lisanti, M.P. Antibiotics That Target Mitochondria Effectively Eradicate Cancer Stem Cells, across Multiple Tumor Types: Treating Cancer like an Infectious Disease. Oncotarget 2015, 6, 4569–4584. [Google Scholar] [CrossRef] [PubMed]
- Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Thiede, C.; Orlando, S.M.; Iacobelli, S.; Ferrara, F.; Fazi, P.; Cicconi, L.; Di Bona, E.; et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N. Engl. J. Med. 2013, 369, 111–121. [Google Scholar] [PubMed] [Green Version]
- Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence That Metformin Exerts Its Anti-Diabetic Effects through Inhibition of Complex 1 of the Mitochondrial Respiratory Chain. Biochem. J. 2000, 348, 607–614. [Google Scholar] [CrossRef] [PubMed]
- Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J.S.; Hileman, E.O.; Plunkett, W.; Keating, M.J.; Huang, P. Inhibition of Mitochondrial Respiration: A Novel Strategy to Enhance Drug-Induced Apoptosis in Human Leukemia Cells by a Reactive Oxygen Species-Mediated Mechanism. J. Biol. Chem. 2003, 278, 37832–37839. [Google Scholar] [CrossRef]
- Hirsch, H.A.; Iliopoulos, D.; Tsichlis, P.N.; Struhl, K. Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission. Cancer Res. 2009, 69, 8832. [Google Scholar] [CrossRef]
- Hadad, S.M.; Coates, P.; Jordan, L.B.; Dowling, R.J.O.; Chang, M.C.; Done, S.J.; Purdie, C.A.; Goodwin, P.J.; Stambolic, V.; Moulder-Thompson, S.; et al. Evidence for Biological Effects of Metformin in Operable Breast Cancer: Biomarker Analysis in a Pre-Operative Window of Opportunity Randomized Trial. Breast Cancer Res. Treat. 2015, 150, 149–155. [Google Scholar] [CrossRef]
- Hirayama, A.; Kami, K.; Sugimoto, M.; Sugawara, M.; Toki, N.; Onozuka, H.; Kinoshita, T.; Saito, N.; Ochiai, A.; Tomita, M.; et al. Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry. Cancer Res. 2009, 69, 4918–4925. [Google Scholar] [CrossRef]
- Walenta, S.; Schroeder, T.; Mueller-Klieser, W. Lactate in Solid Malignant Tumors: Potential Basis of a Metabolic Classification in Clinical Oncology. Curr. Med. Chem. 2004, 11, 2195–2204. [Google Scholar] [CrossRef]
- Birsoy, K.; Possemato, R.; Lorbeer, F.K.; Bayraktar, E.C.; Thiru, P.; Yucel, B.; Wang, T.; Chen, W.W.; Clish, C.B.; Sabatini, D.M. Metabolic Determinants of Cancer Cell Sensitivity to Glucose Limitation and Biguanides. Nature 2014, 508, 108–112. [Google Scholar] [CrossRef]
- Chen, G.; Xu, S.; Renko, K.; Derwahl, M. Metformin Inhibits Growth of Thyroid Carcinoma Cells, Suppresses Self-Renewal of Derived Cancer Stem Cells, and Potentiates the Effect of Chemotherapeutic Agents. J. Clin. Endocrinol. Metab. 2012, 97, E510–E520. [Google Scholar] [CrossRef]
- Song, C.W.; Lee, H.; Dings, R.P.M.; Williams, B.; Powers, J.; dos Santos, T.; Choi, B.H.; Park, H.J. Metformin Kills and Radiosensitizes Cancer Cells and Preferentially Kills Cancer Stem Cells. Sci. Rep. 2012, 2, 362. [Google Scholar] [CrossRef] [PubMed]
- Bao, B.; Wang, Z.; Ali, S.; Ahmad, A.; Azmi, A.S.; Sarkar, S.H.; Banerjee, S.; Kong, D.; Li, Y.; Thakur, S.; et al. Metformin Inhibits Cell Proliferation, Migration and Invasion by Attenuating CSC Function Mediated by Deregulating MiRNAs in Pancreatic Cancer Cells. Cancer Prev. Res. 2012, 5, 355–364. [Google Scholar] [CrossRef] [Green Version]
- Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: From Mechanisms of Action to Therapies. Cell Metab. 2014, 20, 953–966. [Google Scholar] [CrossRef]
- Kordes, S.; Pollak, M.N.; Zwinderman, A.H.; Mathôt, R.A.; Weterman, M.J.; Beeker, A.; Punt, C.J.; Richel, D.J.; Wilmink, J.W. Metformin in Patients with Advanced Pancreatic Cancer: A Double-Blind, Randomised, Placebo-Controlled Phase 2 Trial. Lancet Oncol. 2015, 16, 839–847. [Google Scholar] [CrossRef]
- Home—ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/ (accessed on 30 October 2022).
- Evans, J.M.M.; Donnelly, L.A.; Emslie-Smith, A.M.; Alessi, D.R.; Morris, A.D. Metformin and Reduced Risk of Cancer in Diabetic Patients. Br. Med. J. 2005, 330, 1304–1305. [Google Scholar] [CrossRef]
- Sadeghi, N.; Abbruzzese, J.L.; Yeung, S.C.J.; Hassan, M.; Li, D. Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer. Clin. Cancer Res. 2012, 18, 2905–2912. [Google Scholar] [CrossRef]
- Amin, S.; Mhango, G.; Lin, J.; Aronson, A.; Wisnivesky, J.; Boffetta, P.; Lucas, A.L. Metformin Improves Survival in Patients with Pancreatic Ductal Adenocarcinoma and Pre-Existing Diabetes: A Propensity Score Analysis. Am. J. Gastroenterol. 2016, 111, 1350–1357. [Google Scholar] [CrossRef]
- Bhaw-Luximon, A.; Jhurry, D. Metformin in Pancreatic Cancer Treatment: From Clinical Trials through Basic Research to Biomarker Quantification. J. Cancer Res. Clin. Oncol. 2016, 142, 2159–2171. [Google Scholar] [CrossRef]
- Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.S.; et al. Metformin Inhibits Mitochondrial Complex I of Cancer Cells to Reduce Tumorigenesis. eLife 2014, 3, e02242. [Google Scholar] [CrossRef]
- Bridges, H.R.; Jones, A.J.Y.; Pollak, M.N.; Hirst, J. Effects of Metformin and Other Biguanides on Oxidative Phosphorylation in Mitochondria. Biochem. J. 2014, 462, 475–487. [Google Scholar] [CrossRef]
- Andrzejewski, S.; Gravel, S.-P.; Pollak, M.; St-Pierre, J. Metformin Directly Acts on Mitochondria to Alter Cellular Bioenergetics. Cancer Metab. 2014, 2, 12. [Google Scholar] [CrossRef] [PubMed]
- Scotland, S.; Saland, E.; Skuli, N.; de Toni, F.; Boutzen, H.; Micklow, E.; Sénégas, I.; Peyraud, R.; Peyriga, L.; Théodoro, F.; et al. Mitochondrial Energetic and AKT Status Mediate Metabolic Effects and Apoptosis of Metformin in Human Leukemic Cells. Leukemia 2013, 27, 2129–2138. [Google Scholar] [CrossRef] [PubMed]
- Farge, T.; Saland, E.; de Toni, F.; Aroua, N.; Hosseini, M.; Perry, R.; Bosc, C.; Sugita, M.; Stuani, L.; Fraisse, M.; et al. Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer Discov. 2017, 7, 716–735. [Google Scholar] [CrossRef] [PubMed]
- Candido, S.; Abrams, S.L.; Steelman, L.; Lertpiriyapong, K.; Martelli, A.M.; Cocco, L.; Ratti, S.; Follo, M.Y.; Murata, R.M.; Rosalen, P.L.; et al. Metformin Influences Drug Sensitivity in Pancreatic Cancer Cells. Adv. Biol. Regul. 2018, 68, 13–30. [Google Scholar] [CrossRef]
- Duan, W.; Chen, K.; Jiang, Z.; Chen, X.; Sun, L.; Li, J.; Lei, J.; Xu, Q.; Ma, J.; Li, X.; et al. Desmoplasia Suppression by Metformin-Mediated AMPK Activation Inhibits Pancreatic Cancer Progression. Cancer Lett. 2017, 385, 225–233. [Google Scholar] [CrossRef]
- Qian, W.; Li, J.; Chen, K.; Jiang, Z.; Cheng, L.; Zhou, C.; Yan, B.; Cao, J.; Ma, Q.; Duan, W. Metformin Suppresses Tumor Angiogenesis and Enhances the Chemosensitivity of Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer. Life Sci. 2018, 208, 253–261. [Google Scholar] [CrossRef]
- Rajeshkumar, N.V.; Yabuuchi, S.; Pai, S.G.; de Oliveira, E.; Kamphorst, J.J.; Rabinowitz, J.D.; Tejero, H.; Al-Shahrour, F.; Hidalgo, M.; Maitra, A.; et al. Treatment of Pancreatic Cancer Patient–Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin. Clin. Cancer Res. 2017, 23, 5639–5647. [Google Scholar] [CrossRef]
- Karnevi, E.; Said, K.; Andersson, R.; Rosendahl, A.H. Metformin-Mediated Growth Inhibition Involves Suppression of the IGF-I Receptor Signalling Pathway in Human Pancreatic Cancer Cells. BMC Cancer 2013, 13, 235. [Google Scholar] [CrossRef]
- Alhajala, H.S.; Markley, J.L.; Kim, J.H.; Al-Gizawiy, M.M.; Schmainda, K.M.; Kuo, J.S.; Chitambar, C.R. The Cytotoxicity of Gallium Maltolate in Glioblastoma Cells Is Enhanced by Metformin through Combined Action on Mitochondrial Complex 1. Oncotarget 2020, 11, 1531–1544. [Google Scholar] [CrossRef]
- Cheng, G.; Zielonka, J.; Hardy, M.; Ouari, O.; Chitambar, C.R.; Dwinell, M.B.; Kalyanaraman, B. Synergistic Inhibition of Tumor Cell Proliferation by Metformin and Mito-Metformin in the Presence of Iron Chelators. Oncotarget 2019, 10, 3518–3532. [Google Scholar] [CrossRef]
- Gravel, S.P.; Hulea, L.; Toban, N.; Birman, E.; Blouin, M.J.; Zakikhani, M.; Zhao, Y.; Topisirovic, I.; St-Pierre, J.; Pollak, M. Serine Deprivation Enhances Antineoplastic Activity of Biguanides. Cancer Res. 2014, 74, 7521–7533. [Google Scholar] [CrossRef] [PubMed]
- Kalyanaraman, B.; Cheng, G.; Hardy, M.; Ouari, O.; Sikora, A.; Zielonka, J.; Dwinell, M.B. Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies. Cell Biochem. Biophys. 2017, 75, 311–317. [Google Scholar] [CrossRef] [PubMed]
- Nevala-Plagemann, C.; Hidalgo, M.; Garrido-Laguna, I. From State-of-the-Art Treatments to Novel Therapies for Advanced-Stage Pancreatic Cancer. Nat. Rev. Clin. Oncol. 2020, 17, 108–123. [Google Scholar] [CrossRef] [PubMed]
- Alistar, A.; Morris, B.B.; Desnoyer, R.; Klepin, H.D.; Hosseinzadeh, K.; Clark, C.; Cameron, A.; Leyendecker, J.; D’Agostino, R.; Topaloglu, U.; et al. Safety and Tolerability of the First-in-Class Agent CPI-613 in Combination with Modified FOLFIRINOX in Patients with Metastatic Pancreatic Cancer: A Single-Centre, Open-Label, Dose-Escalation, Phase 1 Trial. Lancet Oncol. 2017, 18, 770–778. [Google Scholar] [CrossRef]
- Giordano, G.; Pancione, M.; Olivieri, N.; Parcesepe, P.; Velocci, M.; di Raimo, T.; Coppola, L.; Toffoli, G.; D’Andrea, M.R. Nano Albumin Bound-Paclitaxel in Pancreatic Cancer: Current Evidences and Future Directions. World J. Gastroenterol. 2017, 23, 5875–5886. [Google Scholar] [CrossRef]
- Fujimura, Y.; Ikenaga, N.; Ohuchida, K.; Setoyama, D.; Irie, M.; Miura, D.; Wariishi, H.; Murata, M.; Mizumoto, K.; Hashizume, M.; et al. Mass Spectrometry-Based Metabolic Profiling of Gemcitabine-Sensitive and Gemcitabine-Resistant Pancreatic Cancer Cells. Pancreas 2014, 43, 311–318. [Google Scholar] [CrossRef]
- Zhao, H.; Duan, Q.; Zhang, Z.; Li, H.; Wu, H.; Shen, Q.; Wang, C.; Yin, T. Up-Regulation of Glycolysis Promotes the Stemness and EMT Phenotypes in Gemcitabine-Resistant Pancreatic Cancer Cells. J. Cell. Mol. Med. 2017, 21, 2055–2067. [Google Scholar] [CrossRef]
- Tréhoux, S.; Duchêne, B.; Jonckheere, N.; van Seuningen, I. The MUC1 Oncomucin Regulates Pancreatic Cancer Cell Biological Properties and Chemoresistance. Implication of P42–44 MAPK, Akt, Bcl-2 and MMP13 Pathways. Biochem. Biophys. Res. Commun. 2015, 456, 757–762. [Google Scholar] [CrossRef]
- Ji, S.; Qin, Y.; Liang, C.; Huang, R.; Shi, S.; Liu, J.; Jin, K.; Liang, D.; Xu, W.; Zhang, B.; et al. FBW7 (F-Box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer. Clin. Cancer Res. 2016, 22, 3950–3960. [Google Scholar] [CrossRef]
- Lai, I.L.; Chou, C.C.; Lai, P.T.; Fang, C.S.; Shirley, A.L.; Yan, R.; Mo, X.; Bloomston, M.; Kulp, S.K.; Bekaii-Saab, T.; et al. Targeting the Warburg Effect with a Novel Glucose Transporter Inhibitor to Overcome Gemcitabine Resistance in Pancreatic Cancer Cells. Carcinogenesis 2014, 35, 2203–2213. [Google Scholar] [CrossRef]
- Xia, G.; Wang, H.; Song, Z.; Meng, Q.; Huang, X.; Huang, X. Gambogic Acid Sensitizes Gemcitabine Efficacy in Pancreatic Cancer by Reducing the Expression of Ribonucleotide Reductase Subunit-M2 (RRM2). J. Exp. Clin. Cancer Res. 2017, 36, 107. [Google Scholar] [CrossRef] [PubMed]
- Jin, X.; Pan, Y.; Wang, L.; Ma, T.; Zhang, L.; Tang, A.H.; Billadeau, D.D.; Wu, H.; Huang, H. Fructose-1,6-Bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1–MAPK Interaction. Cancer Res. 2017, 77, 4328–4341. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, R.; Lai, L.A.; Sullivan, Y.; Wong, M.; Wang, L.; Riddell, J.; Jung, L.; Pillarisetty, V.G.; Brentnall, T.A.; Pan, S. Disrupting Glutamine Metabolic Pathways to Sensitize Gemcitabine-Resistant Pancreatic Cancer. Sci. Rep. 2017, 7, 7950. [Google Scholar] [CrossRef]
- Zhang, Z.; Duan, Q.; Zhao, H.; Liu, T.; Wu, H.; Shen, Q.; Wang, C.; Yin, T. Gemcitabine Treatment Promotes Pancreatic Cancer Stemness through the Nox/ROS/NF-ΚB/STAT3 Signaling Cascade. Cancer Lett. 2016, 382, 53–63. [Google Scholar] [CrossRef]
- Zarei, M.; Lal, S.; Parker, S.J.; Nevler, A.; Vaziri-Gohar, A.; Dukleska, K.; Mambelli-Lisboa, N.C.; Moffat, C.; Blanco, F.F.; Chand, S.N.; et al. Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. Cancer Res. 2017, 77, 4460–4471. [Google Scholar] [CrossRef] [PubMed]
- Hessmann, E.; Patzak, M.S.; Klein, L.; Chen, N.; Kari, V.; Ramu, I.; Bapiro, T.E.; Frese, K.K.; Gopinathan, A.; Richards, F.M.; et al. Fibroblast Drug Scavenging Increases Intratumoural Gemcitabine Accumulation in Murine Pancreas Cancer. Gut 2018, 67, 497–507. [Google Scholar] [CrossRef]
- Sherman, M.H.; Yu, R.T.; Engle, D.D.; Ding, N.; Atkins, A.R.; Tiriac, H.; Collisson, E.A.; Connor, F.; van Dyke, T.; Kozlov, S.; et al. Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy. Cell 2014, 159, 80–93. [Google Scholar] [CrossRef]
- Broekgaarden, M.; Anbil, S.; Bulin, A.L.; Obaid, G.; Mai, Z.; Baglo, Y.; Rizvi, I.; Hasan, T. Modulation of Redox Metabolism Negates Cancer-Associated Fibroblasts-Induced Treatment Resistance in a Heterotypic 3D Culture Platform of Pancreatic Cancer. Biomaterials 2019, 222, 119421. [Google Scholar] [CrossRef]
- Cullis, J.; Siolas, D.; Avanzi, A.; Barui, S.; Maitra, A.; Bar-Sagi, D. Macropinocytosis of Nab-Paclitaxel Drives Macrophage Activation in Pancreatic Cancer. Cancer Immunol. Res. 2017, 5, 182–190. [Google Scholar] [CrossRef]
- Dholakia, A.S.; Chaudhry, M.; Leal, J.P.; Chang, D.T.; Raman, S.P.; Hacker-Prietz, A.; Su, Z.; Pai, J.; Oteiza, K.E.; Griffith, M.E.; et al. Baseline Metabolic Tumor Volume and Total Lesion Glycolysis Are Associated with Survival Outcomes in Patients with Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 2014, 89, 539–546. [Google Scholar] [CrossRef]
- Kurahara, H.; Maemura, K.; Mataki, Y.; Sakoda, M.; Iino, S.; Kawasaki, Y.; Arigami, T.; Mori, S.; Kijima, Y.; Ueno, S.; et al. Significance of 18F-Fluorodeoxyglucose (FDG) Uptake in Response to Chemoradiotherapy for Pancreatic Cancer. Ann. Surg. Oncol. 2019, 26, 644–651. [Google Scholar] [CrossRef] [PubMed]
- Coleman, M.C.; Asbury, C.R.; Daniels, D.; Du, J.; Aykin-Burns, N.; Smith, B.J.; Li, L.; Spitz, D.R.; Cullen, J.J. 2-Deoxy-d-Glucose Causes Cytotoxicity, Oxidative Stress, and Radiosensitization in Pancreatic Cancer. Free Radic. Biol. Med. 2008, 44, 322–331. [Google Scholar] [CrossRef] [PubMed]
- Zahra, A.; Fath, M.A.; Opat, E.; Mapuskar, K.A.; Bhatia, S.K.; Ma, D.C.; Iii, S.N.R.; Snyders, T.P.; Chenard, C.A.; Eichenberger-Gilmore, J.M.; et al. Consuming a Ketogenic Diet While Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials. Radiat. Res. 2017, 187, 743–754. [Google Scholar] [CrossRef] [PubMed]
- Wallace, D.C.; Fan, W. Energetics, Epigenetics, Mitochondrial Genetics. Mitochondrion 2010, 10, 12–31. [Google Scholar] [PubMed]
- Phillips, D.; Covian, R.; Aponte, A.M.; Glancy, B.; Taylor, J.F.; Chess, D.; Balaban, R.S. Regulation of Oxidative Phosphorylation Complex Activity: Effects of Tissue-Specific Metabolic Stress within an Allometric Series and Acute Changes in Workload. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 302, R1034–R1048. [Google Scholar] [CrossRef]
- Wallace, D.C.; Fan, W.; Procaccio, V. Mitochondrial Energetics and Therapeutics. Annu. Rev. Pathol. Mech. Dis. 2010, 5, 297–348. [Google Scholar] [CrossRef]
- Wallace, D.C. A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine. Annu. Rev. Genet. 2005, 39, 359–407. [Google Scholar] [CrossRef]
- Wallace, D.C. The Epigenome and the Mitochondrion: Bioenergetics and the Environment. Genes Dev. 2010, 24, 1571–1573. [Google Scholar] [CrossRef]
- Bonuccelli, G.; Whitaker-Menezes, D.; Castello-Cros, R.; Pavlides, S.; Pestell, R.G.; Fatatis, A.; Witkiewicz, A.K.; vander Heiden, M.G.; Migneco, G.; Chiavarina, B.; et al. The Reverse Warburg Effect: Glycolysis Inhibitors Prevent the Tumor Promoting Effects of Caveolin-1 Deficient Cancer Associated Fibroblasts. Cell Cycle 2010, 9, 1960–1971. [Google Scholar] [CrossRef]
- Pavlides, S.; Tsirigos, A.; Vera, I.; Flomenberg, N.; Frank, P.G.; Casimiro, M.C.; Wang, C.; Pestell, R.G.; Martinez-Outschoorn, U.E.; Howell, A.; et al. Transcriptional Evidence for the “Reverse Warburg Effect” in Human Breast Cancer Tumor Stroma and Metastasis: Similarities with Oxidative Stress, Inflammation, Alzheimer’s Disease, and “Neuron-Glia Metabolic Coupling”. Aging 2010, 2, 185–199. [Google Scholar] [CrossRef]
- Castello-Cros, R.; Bonuccelli, G.; Molchansky, A.; Capozza, F.; Witkiewicz, A.K.; Birbe, R.C.; Howell, A.; Pestell, R.G.; Whitaker-Menezes, D.; Sotgia, F.; et al. Matrix Remodeling Stimulates Stromal Autophagy, “Fueling” Cancer Cell Mitochondrial Metabolism and Metastasis. Cell Cycle 2011, 10, 2021–2034. [Google Scholar] [CrossRef] [PubMed]
- Capparelli, C.; Guido, C.; Whitaker-Menezes, D.; Bonuccelli, G.; Balliet, R.; Pestell, T.G.; Goldberg, A.F.; Pestell, R.G.; Howell, A.; Sneddon, S.; et al. Autophagy and Senescence in Cancer-Associated Fibroblasts Metabolically Supports Tumor Growth and Metastasis, via Glycolysis and Ketone Production. Cell Cycle 2012, 11, 2285–2302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pavlides, S.; Vera, I.; Gandara, R.; Sneddon, S.; Pestell, R.G.; Mercier, I.; Martinez-Outschoorn, U.E.; Whitaker-Menezes, D.; Howell, A.; Sotgia, F.; et al. Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and Metastasis via Oxidative Stress, Mitophagy, and Aerobic Glycolysis. Antioxid. Redox Signal. 2012, 16, 1264–1284. [Google Scholar] [CrossRef]
- Pagliarini, D.J.; Calvo, S.E.; Chang, B.; Sheth, S.A.; Vafai, S.B.; Ong, S.E.; Walford, G.A.; Sugiana, C.; Boneh, A.; Chen, W.K.; et al. A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology. Cell 2008, 134, 112–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Mitochondrial | Sample ID | Protein Change | Mutation Type | Variant Type |
---|---|---|---|---|
MT-CO1 | ICGC_0054 | L367P | Missense Mutation | SNP |
ICGC_0389 | E266Nfs | Frame Shift Deletion | DEL | |
ICGC_0067 | G269E | Missense Mutation | SNP | |
ICGC_0016 | G457S | Missense Mutation | SNP | |
ICGC_0067 | G160 * | Nonsense Mutation | SNP | |
ICGC_0285 | R5H | Missense Mutation | SNP | |
ICGC_0046 | D445N | Missense Mutation | SNP | |
ICGC_0367 | D51N | Missense Mutation | SNP | |
GARV_0671 | V456M | Missense Mutation | SNP | |
GARV_0671 | V28I | Missense Mutation | SNP | |
ICGC_0006 | I247T | Missense Mutation | SNP | |
ICGC_0102 | T181P | Missense Mutation | SNP | |
ICGC_0139 | S489P | Missense Mutation | SNP | |
ICGC_0154 | A89T | Missense Mutation | SNP | |
ICGC_0188 | V155A | Missense Mutation | SNP | |
ICGC_0225 | A3P | Missense Mutation | SNP | |
ICGC_0504 | G42S | Missense Mutation | SNP | |
ICGC_0112 | P500Hfs | Frame Shift Deletion | DEL | |
ICGC_0137 | A133T | Missense Mutation | SNP | |
ICGC_0245 | Y371H | Missense Mutation | SNP | |
ICGC_0328 | M278T | Missense Mutation | SNP | |
IDH2 | TCGA-IB-7651-01 | G201D | Missense Mutation | SNP |
TCGA-IB-7651-01 | L143M | Missense Mutation | SNP | |
TCGA-IB-7651-01 | K133R | Missense Mutation | SNP | |
TCGA-IB-AAUO-01 | R288L | Missense Mutation | SNP | |
TCGA-3A-A9IH-01 | A239V | Missense Mutation | SNP | |
TCGA-IB-7651-01 | G201D | Missense Mutation | SNP | |
TCGA-IB-7651-01 | L143M | Missense Mutation | SNP | |
TCGA-IB-7651-01 | K133R | Missense Mutation | SNP | |
MT-ND3 | ICGC_0361 | V88A | Missense Mutation | SNP |
ICGC_0075 | A4T | Missense Mutation | SNP | |
ICGC_0343 | W113 | Missense Mutation | SNP | |
ICGC_0008 | E38K | Missense Mutation | SNP | |
ICGC_0271 | A14T | Missense Mutation | SNP | |
ICGC_0350 | I96T | Missense Mutation | SNP |
Molecular Target | Mitochondrial Inhibitor | Combination with | PDAC Stage | Clinical Trial | NCT Number | Outcome Measures | Status |
---|---|---|---|---|---|---|---|
OXPHOS (Complex1) | Metformin hydrochloride | Resectable | II | NCT02978547 | Metformin effect in PDAC proliferation, glucose and insulin metabolism | Unknown | |
Metformin | Aspirin, ACE inhibitors, B-blockers | Patients underwent surgical resection or chemotherapy | NA | NCT04245644 | DFS; OS | Recruiting | |
Metformin | PDAC patients with hyperglycemia | NA | NCT05132244 | ORR; PFS; OS | Not yet recruiting | ||
Metformin | Gemcitabine, Erlotinib | Locally advanced or metastatic | II | NCT01210911 | PFS; ORR; toxicity | Completed | |
Metformin | Oxaliplatin, Fluorouracil, Leucovorin calcium | Metastatic | II | NCT01666730 | ORR and clinical benefit rate based on CT and MRI | Completed | |
Metformin | Stereotactic radiosurgery | Borderline-resectable or locally advanced | Early phase I | NCT02153450 | Dose-limiting toxicity; PFS using RECIST | Completed | |
Metformin | Gemcitabine, Nab-paclitaxel, dietary supplement | Unresectable | I | NCT02336087 | Feasibility of Metformin combinations | Completed | |
Metformin | Rapamycin | Metastatic, stable disease after FOLFIRINOX or Gemcitabine treatment | I | NCT02048384 | Feasibility and safety | Completed | |
Metformin | Paclitaxel | Locally advanced or metastatic, after Gemcitabine failure | II | NCT01971034 | Time to progression; biochemical response estimation | Completed | |
OXPHOS (complex IV) | Arsenic trioxide | Locally advanced or metastatic, after Gemcitabine failure | II | NCT00053222 | ORR | Completed | |
PDH and KGDH | Devimistat (CPI-613) | mFOLFIRINOX | Unresectable | II | NCT03699319 | OS; MTD; PFS | Completed |
Devimistat (CPI-613) | mFOLFIRINOX | Metastatic | III | NCT03504423 | OS; PFS; ORR | Completed | |
Devimistat (CPI-613) | Gemcitabine | I | NCT05325281 | Maximum tolerated dose; toxicity | Recruiting |
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Padinharayil, H.; Rai, V.; George, A. Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy. Cancers 2023, 15, 1070. https://doi.org/10.3390/cancers15041070
Padinharayil H, Rai V, George A. Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy. Cancers. 2023; 15(4):1070. https://doi.org/10.3390/cancers15041070
Chicago/Turabian StylePadinharayil, Hafiza, Vikrant Rai, and Alex George. 2023. "Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy" Cancers 15, no. 4: 1070. https://doi.org/10.3390/cancers15041070