Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential

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 de-pends 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. In-terestingly, 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 potentialThis research was funded by the Pancreatic Cancer Research Fund, 2015 Award Round (P.S., C.H.); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n 602783 (CAM-PaC) (C.H.), theWorldwide Cancer Research Charity together with Fundación Científica Asociación Española contra el Cáncer (FCAECC) (19-0250) (P.S.); A Fero Foundation grant and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC) (B.S.J.); and the Instituto de Salud Carlos III through the Miguel Servet Program (CP16/00121) and Fondo de Investigaciones Sanitarias (PI17/00082) (both co-financed by European funds (FSE: “El FSE invierte en tu futuro” and FEDER: “Una manera de hacer Europa,” respectively) (P.S.