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Article

Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential

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Translational Research Unit, Hospital Universitario Miguel Servet, IIS Aragon, 50009 Zaragoza, Spain
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Centre for Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
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Department of Biochemistry, School of Medicine, Instituto de Investigaciones Biomédicas (IIBm) “Alberto Sols” CSIC-UAM, Autónoma University of Madrid (UAM), 28029 Madrid, Spain
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Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
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Department of Zoology, Genetics and Physical Anthropology, Veterinary Faculty, Universidad de Santiago de Compostela, 27002 Lugo, Spain
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Center for Single-Cell Omics, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
*
Authors to whom correspondence should be addressed.
Shared first authorship.
Academic Editor: Stephen J. Beebe
Cancers 2021, 13(4), 698; https://doi.org/10.3390/cancers13040698
Received: 16 January 2021 / Revised: 31 January 2021 / Accepted: 5 February 2021 / Published: 9 February 2021
(This article belongs to the Special Issue Tumor and Metabolism)
Due to their intrinsic aggressiveness, cancer stem cells (CSCs) represent an essential target for the design of effective treatments against pancreatic cancer, one of the deadliest tumors. As pancreatic CSCs are particularly dependent on the activity of their mitochondria, we here focus on mitochondrial dynamics as a critical process in the homeostasis of these organelles. We find that pancreatic CSCs rely on mitochondrial fission, and its pharmacological inhibition by mDivi-1 resulted in the accumulation of dysfunctional mitochondria, provoking an energy crisis and cell death in this subpopulation. Consequently, mDivi-1 blocked cellular functions related to cancer aggressiveness such as in vivo tumorigenicity, invasiveness, and chemoresistance. Our data suggest that the inhibition of mitochondrial fission represents a promising target for designing new multimodal therapies to fight pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential. View Full-Text
Keywords: mitochondria; mitochondrial dynamics; mitochondrial fission; cancer stem cells; CD133; DRP1; energy crisis; PDAC; pancreatic cancer mitochondria; mitochondrial dynamics; mitochondrial fission; cancer stem cells; CD133; DRP1; energy crisis; PDAC; pancreatic cancer
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MDPI and ACS Style

Courtois, S.; de Luxán-Delgado, B.; Penin-Peyta, L.; Royo-García, A.; Parejo-Alonso, B.; Jagust, P.; Alcalá, S.; Rubiolo, J.A.; Sánchez, L.; Sainz, B., Jr.; Heeschen, C.; Sancho, P. Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential. Cancers 2021, 13, 698. https://doi.org/10.3390/cancers13040698

AMA Style

Courtois S, de Luxán-Delgado B, Penin-Peyta L, Royo-García A, Parejo-Alonso B, Jagust P, Alcalá S, Rubiolo JA, Sánchez L, Sainz B Jr., Heeschen C, Sancho P. Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential. Cancers. 2021; 13(4):698. https://doi.org/10.3390/cancers13040698

Chicago/Turabian Style

Courtois, Sarah, Beatriz de Luxán-Delgado, Laure Penin-Peyta, Alba Royo-García, Beatriz Parejo-Alonso, Petra Jagust, Sonia Alcalá, Juan A. Rubiolo, Laura Sánchez, Bruno Sainz Jr., Christopher Heeschen, and Patricia Sancho. 2021. "Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential" Cancers 13, no. 4: 698. https://doi.org/10.3390/cancers13040698

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