Special Issue "Tumor Metabolome: Therapeutic Opportunities Targeting Cancer Metabolic Reprogramming"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 July 2020.

Special Issue Editors

Prof. Dr. Javier Marquez

Guest Editor
1. Canceromics Lab, Departmento de Biología Molecular y Bioquímica, Faculty of Sciences, University of Malaga, 29071 Málaga, Spain
2. Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain
Interests: canceromics; cancer metabolic reprogramming; gene therapy; tumor nitrogen metabolism
Prof. Dr. José M. Matés
Website
Guest Editor
1. Canceromics Lab, Departmento de Biología Molecular y Bioquímica, Faculty of Sciences, University of Malaga, 29071 Málaga, Spain
2. Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain
Interests: cancer mitochondrial metabolism; oxidative stress; tumor-specific isoenzymes; combined therapies against cancer

Special Issue Information

Dear Colleagues,

Cancer cells have metabolic requirements that separate them from normal cells and render them vulnerable to drugs that target these processes. The altered metabolism exhibited by most tumor cells is a hallmark of cancer. Pioneering works studying the differential metabolic traits of cancer cells firstly classified tumors as glucose and nitrogen traps, thus reflecting their ability to avidly consume both nutrients. In recent years, metabolic studies using omics technologies are more precisely unveiling the tumor metabolome and cancer-specific metabolomic signatures.

Despite the sound advances in knowledge and the rapid progress in the field of cancer metabolic reprogramming, this information needs to be translated into a more successful class of cancer therapeutic strategies. Furthermore, the mechanims that control the metabolic phenotype of specific tumors have not been fully understood, and the biological functions of many cancer-relevant proteins have yet to be explored. These issues need to be addressed in order to improve drug design and to overcome the drug resistance phenomenon frequently found in cancer therapy. In this Special Issue of Cancers, we aim to stimulate discussions on these topics, whilst allowing an updated account of relevant works on the tumor metabolome by bringing together expert opinions from across the field. We welcome submissions that cover any relevant topic, including metabolite addiction in cancer cells, cancer metabolic rewiring, cancer metabolic remodelling by tumor-specific isoenzymes, cancer-specific bionergetic alterations, new metabolic functions of tumor suppresor genes and oncogenes, mechanisms of metabolic dysregulation in cancers, and new therapeutic approaches targeting cancer metabolism.

Prof. Dr. Javier Marquez
Prof. Dr. José M. Matés
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Oncometabolites
  • Glutaminolysis
  • Tumor metabolome
  • Cancer metabolic reprogramming
  • Tumor-specific isoenzymes
  • Cancer biomarkers
  • Therapeutic targets

Published Papers (7 papers)

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Research

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Open AccessArticle
Metabolic Reprogramming in Metastatic Melanoma with Acquired Resistance to Targeted Therapies: Integrative Metabolomic and Proteomic Analysis
Cancers 2020, 12(5), 1323; https://doi.org/10.3390/cancers12051323 - 22 May 2020
Abstract
Treatments of metastatic melanoma underwent an impressive development over the past few years, with the emergence of small molecule inhibitors targeting mutated proteins, such as BRAF, NRAS, or cKIT. However, since a significant proportion of patients acquire resistance to these therapies, new strategies [...] Read more.
Treatments of metastatic melanoma underwent an impressive development over the past few years, with the emergence of small molecule inhibitors targeting mutated proteins, such as BRAF, NRAS, or cKIT. However, since a significant proportion of patients acquire resistance to these therapies, new strategies are currently being considered to overcome this issue. For this purpose, melanoma cell lines with mutant BRAF, NRAS, or cKIT and with acquired resistances to BRAF, MEK, or cKIT inhibitors, respectively, were investigated using both 1H-NMR-based metabonomic and protein microarrays. The 1H-NMR profiles highlighted a similar go and return pattern in the metabolism of the BRAF, NRAS, and cKIT mutated cell lines. Indeed, melanoma cells exposed to mutation-specific inhibitors underwent metabolic disruptions following acute exposure but partially recovered their basal metabolism in long-term exposure, most likely acquiring resistance skills. The protein microarrays inquired about the potential cellular mechanisms used by the resistant cells to escape drug treatment, by showing decreased levels of proteins linked to the drug efficacy, especially in the downstream part of the MAPK signaling pathway. Integrating metabonomic and proteomic findings revealed some metabolic pathways (i.e., glutaminolysis, choline metabolism, glutathione production, glycolysis, oxidative phosphorylation) and key proteins (i.e., EPHA2, DUSP4, and HIF-1A) as potential targets to discard drug resistance. Full article
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Open AccessArticle
ACLY (ATP Citrate Lyase) Mediates Radioresistance in Head and Neck Squamous Cell Carcinomas and is a Novel Predictive Radiotherapy Biomarker
Cancers 2019, 11(12), 1971; https://doi.org/10.3390/cancers11121971 - 07 Dec 2019
Cited by 1
Abstract
Radiotherapy is an important treatment modality of head and neck squamous cell carcinomas (HNSCC). Multiple links have been described between the metabolic activity of tumors and their clinical outcome. Here we test the hypothesis that metabolic features determine radiosensitivity, explaining the relationship between [...] Read more.
Radiotherapy is an important treatment modality of head and neck squamous cell carcinomas (HNSCC). Multiple links have been described between the metabolic activity of tumors and their clinical outcome. Here we test the hypothesis that metabolic features determine radiosensitivity, explaining the relationship between metabolism and clinical outcome. Radiosensitivity of 14 human HNSCC cell lines was determined using colony forming assays and the expression profile of approximately 200 metabolic and cancer-related genes was generated using targeted RNA sequencing by single molecule molecular inversion probes. Results: Correlation between radiosensitivity data and expression profiles yielded 18 genes associated with radiosensitivity or radioresistance, of which adenosine triphosphate (ATP) citrate lyase (ACLY) was of particular interest. Pharmacological inhibition of ACLY caused an impairment of DNA damage repair, specifically homologous recombination, and lead to radiosensitization in HNSCC cell lines. Examination of a The Cancer Genome Atlas (TCGA) cohort of HNSCC patients revealed that high expression of ACLY was predictive for radiotherapy failure, as it was only associated with poor overall survival in patients who received radiotherapy (hazard ratio of 2.00, 95% CI: 1.12–3.55; p = 0.0184). These data were further validated in an independent cohort of HNSCC patients treated with chemoradiation. Furthermore, patients with poor locoregional control after radiotherapy have significantly higher nuclear ACLY protein levels. Together, we here show that ACLY affects DNA damage repair, and is a predictive factor for radiotherapy outcome in HNSCC. Full article
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Open AccessArticle
The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression
Cancers 2019, 11(10), 1610; https://doi.org/10.3390/cancers11101610 - 22 Oct 2019
Cited by 2
Abstract
Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the [...] Read more.
Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies. Full article
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Open AccessArticle
HSF1 Regulates Mevalonate and Cholesterol Biosynthesis Pathways
Cancers 2019, 11(9), 1363; https://doi.org/10.3390/cancers11091363 - 13 Sep 2019
Abstract
Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in [...] Read more.
Heat shock factor 1 (HSF1) is an essential transcription factor in cellular adaptation to various stresses such as heat, proteotoxic stress, metabolic stress, reactive oxygen species, and heavy metals. HSF1 promotes cancer development and progression, and increased HSF1 levels are frequently observed in multiple types of cancers. Increased activity in the mevalonate and cholesterol biosynthesis pathways, which are very important for cancer growth and progression, is observed in various cancers. However, the functional role of HSF1 in the mevalonate and cholesterol biosynthesis pathways has not yet been investigated. Here, we demonstrated that the activation of RAS-MAPK signaling through the overexpression of H-RasV12 increased HSF1 expression and the cholesterol biosynthesis pathway. In addition, the activation of HSF1 was also found to increase cholesterol biosynthesis. Inversely, the suppression of HSF1 by the pharmacological inhibitor KRIBB11 and short-hairpin RNA (shRNA) reversed H-RasV12-induced cholesterol biosynthesis. From the standpoint of therapeutic applications for hepatocellular carcinoma (HCC) treatment, HSF1 inhibition was shown to sensitize the antiproliferative effects of simvastatin in HCC cells. Overall, our findings demonstrate that HSF1 is a potential target for statin-based HCC treatment. Full article
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Open AccessArticle
Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer
Cancers 2019, 11(5), 686; https://doi.org/10.3390/cancers11050686 - 16 May 2019
Cited by 3
Abstract
Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get [...] Read more.
Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. BC and control tissue samples (n = 44) from the same patients were analyzed by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance and microarrays techniques. Besides, urinary profiling study (n = 35) was performed in the same patients to identify a metabolomic profile, linked with BC tissue hallmarks, as a potential non-invasive approach for BC diagnosis. The metabolic profile allowed for the classification of BC tissue samples with a sensitivity and specificity of 100%. The most discriminant metabolites for BC tissue samples reflected alterations in amino acids, glutathione, and taurine metabolic pathways. Transcriptomic data supported metabolomic results and revealed a predominant downregulation of metabolic genes belonging to phosphorylative oxidation, tricarboxylic acid cycle, and amino acid metabolism. The urinary profiling study showed a relation with taurine and other amino acids perturbed pathways observed in BC tissue samples, and classified BC from non-tumor urine samples with good sensitivities (91%) and specificities (77%). This urinary profile could be used as a non-invasive tool for BC diagnosis and follow-up. Full article
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Review

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Open AccessReview
Targeting Glutamine Addiction in Gliomas
Cancers 2020, 12(2), 310; https://doi.org/10.3390/cancers12020310 - 29 Jan 2020
Abstract
The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant [...] Read more.
The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas. Full article
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Open AccessReview
Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment
Cancers 2019, 11(6), 750; https://doi.org/10.3390/cancers11060750 - 29 May 2019
Cited by 10Correction
Abstract
Cancer is a metabolic disease in which abnormally proliferating cancer cells rewire metabolic pathways in the tumor microenvironment (TME). Molecular reprogramming in the TME helps cancer cells to fulfill elevated metabolic demands for bioenergetics and cellular biosynthesis. One of the ways through which [...] Read more.
Cancer is a metabolic disease in which abnormally proliferating cancer cells rewire metabolic pathways in the tumor microenvironment (TME). Molecular reprogramming in the TME helps cancer cells to fulfill elevated metabolic demands for bioenergetics and cellular biosynthesis. One of the ways through which cancer cell achieve this is by regulating the expression of metabolic enzymes. Lactate dehydrogenase (LDH) is the primary metabolic enzyme that converts pyruvate to lactate and vice versa. LDH also plays a significant role in regulating nutrient exchange between tumor and stroma. Thus, targeting human lactate dehydrogenase for treating advanced carcinomas may be of benefit. LDHA and LDHB, two isoenzymes of LDH, participate in tumor stroma metabolic interaction and exchange of metabolic fuel and thus could serve as potential anticancer drug targets. This article reviews recent research discussing the roles of lactate dehydrogenase in cancer metabolism. As molecular regulation of LDHA and LDHB in different cancer remains obscure, we also review signaling pathways regulating LDHA and LDHB expression. We highlight on the role of small molecule inhibitors in targeting LDH activity and we emphasize the development of safer and more effective LDH inhibitors. We trust that this review will also generate interest in designing combination therapies based on LDH inhibition, with LDHA being targeted in tumors and LDHB in stromal cells for better treatment outcome. Full article
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