RT Journal Article
T1 Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential
A1 Courtois, Sarah
A1 Luxán Delgado, Beatriz de
A1 Penin Peyta, Laure
A1 Royo García, Alba
A1 Pareja Alonso, Beatriz
A1 Jagust, Petra
A1 Alcalá, Sonia
A1 Rubiolo Gaytán, Juan Andrés
A1 Sánchez Piñón, Laura
A1 Sainz Anding, Bruno
A1 Heeschen, Christopher
A1 Sancho, Patricia
K1 Mitochondria
K1 Mitochondrial dynamics
K1 Mitochondrial fission
K1 Cancer stem cells
K1 CD133
K1 DRP1
K1 Energy crisis
K1 PDAC
K1 Pancreatic cancer
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 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
PB MDPI
YR 2021
FD 2021
LK http://hdl.handle.net/10347/24423
UL http://hdl.handle.net/10347/24423
LA eng
NO Cancers 2021, 13(4), 698; https://doi.org/10.3390/cancers13040698
NO This 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.), the Worldwide 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.)
DS Minerva
RD 22 abr 2026