RT Journal Article
SR Electronic
T1 Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.17.426987
DO 10.1101/2021.01.17.426987
A1 Sarah Courtois
A1 Beatriz de Luxán-Delgado
A1 Laure Penin-Peyta
A1 Alba Royo-García
A1 Beatriz Parejo-Alonso
A1 Petra Jagust
A1 Sonia Alcalá
A1 Juan A. Rubiolo
A1 Laura Sánchez
A1 Bruno Sainz, Jr
A1 Christopher Heeschen
A1 Patricia Sancho
YR 2021
UL http://biorxiv.org/content/early/2021/01/17/2021.01.17.426987.abstract
AB 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 aimed 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 observed that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating activation of mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to accumulation of dysfunctional mitochondria and 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.Simple Summary 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 found that pancreatic CSCs rely on mitochondrial fission, and its pharmacological inhibition by mDivi-1 resulted in the accumulation of dysfunctional mitochondria, provoking 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 inhibition of mitochondrial fission represents a promising target for designing new multimodal therapies to fight pancreatic cancer.Competing Interest StatementThe authors have declared no competing interest.