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  3. mCAUSE: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes

mCAUSE: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes

  • iScience. 2024 Sep 3;27(9):110880. doi: 10.1016/j.isci.2024.110880.
Daisuke Murata 1,  Fumiya Ito 1,  Gongyu Tang 2 3,  Wakiko Iwata 1,  Nelson Yeung 1,  Junior J West 1,  Andrew J Ewald 1 4 5 6,  Xiaowei Wang 2 3,  Miho Iijima 1,  Hiromi Sesaki 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Department of Pharmacology and Regenerative Medicine, University of Illinois Chicago, Chicago, IL, USA.
  • 3 University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA.
  • 4 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
PMID: 39310760 DOI: 10.1016/j.isci.2024.110880
Abstract

Substantial changes in energy metabolism are a hallmark of pancreatic Cancer. To adapt to hypoxic and nutrient-deprived microenvironments, pancreatic Cancer cells remodel their bioenergetics from Oxidative Phosphorylation to glycolysis. This bioenergetic shift makes mitochondria an Achilles' heel. Since mitochondrial function remains essential for pancreatic Cancer cells, further depleting mitochondrial energy production is an appealing treatment target. However, identifying effective mitochondrial targets for treatment is challenging. Here, we developed an approach, mitochondria-targeted Cancer analysis using survival and expression (mCAUSE), to prioritize target proteins from the entire mitochondrial proteome. Selected proteins were further tested for their impact on pancreatic Cancer cell phenotypes. We discovered that targeting a dynamin-related GTPase, OPA1, which controls mitochondrial fusion and cristae, effectively suppresses pancreatic Cancer activities. Remarkably, when combined with a mutation-specific KRAS inhibitor, OPA1 inhibition showed a synergistic effect. Our findings offer a therapeutic strategy against pancreatic Cancer by simultaneously targeting mitochondria dynamics and KRAS signaling.

Keywords

Cancer; Cell biology; Molecular biology.

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