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Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth

Sarbajeet Nagdas1, Jennifer A Kashatus1, Aldo Nascimento1

  • 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.

Cell Reports
|August 15, 2019
PubMed

Insights

Dynamin-related protein 1 (Drp1) is crucial for KRas-driven tumor growth, supporting both glycolysis and mitochondrial function. Its deletion improves survival in pancreatic cancer models, highlighting its complex role in cancer progression.

Area of Science:

  • Mitochondrial dynamics
  • Oncogenic signaling pathways
  • Cancer metabolism

Background:

  • Mitochondria maintain homeostasis through fission and fusion; dysregulation is common in tumors.
  • Ectopic HRas promoted mitochondrial fragmentation and tumor growth via Drp1 phosphorylation.
  • The role of Drp1 in endogenous KRas-driven cancers was previously unknown.

Purpose of the Study:

  • To investigate the role of Dynamin-related protein 1 (Drp1) in KRas-driven tumor growth.
  • To determine Drp1's impact on cancer metabolism, specifically glycolysis and mitochondrial function.
  • To assess the therapeutic potential of targeting Drp1 in KRas-driven pancreatic cancer.

Main Methods:

  • Utilized KRas-driven anchorage-independent growth assays in fibroblasts and pancreatic cancer cell lines.
  • Assessed the effect of Drp1 deletion on tumor growth and survival in a KRas-driven pancreatic cancer model.
  • Investigated Drp1's regulation of glycolytic flux and hexokinase 2 (HK2) expression.
  • Analyzed metabolic profiles of tumors with and without Drp1 deletion.

Main Results:

  • Drp1 is essential for KRas-driven anchorage-independent growth and promotes glycolytic flux partly via HK2 regulation.
  • Drp1 deletion significantly enhances survival in a KRas-driven pancreatic cancer model, with strong selective pressure against its complete absence.
  • Tumors lacking Drp1 exhibit restored glycolysis but impaired mitochondrial metabolism, indicating dual roles.
  • Drp1 supports both glycolysis and mitochondrial function through distinct mechanisms in KRas-driven tumors.

Conclusions:

  • Drp1 plays critical, dual roles in KRas-driven tumor progression by supporting both glycolysis and mitochondrial function.
  • Targeting Drp1 presents a potential therapeutic strategy for KRas-driven pancreatic cancers.
  • Understanding Drp1's complex regulation of cancer metabolism is key for developing effective treatments.
Keywords:
Drp1KRasmetabolismmitochondriapancreatic cancer

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