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

Cell Rep. 2019 Aug 13;28(7):1845-1859.e5. doi: 10.1016/j.celrep.2019.07.031.


Mitochondria undergo fission and fusion to maintain homeostasis, and tumors exhibit the dysregulation of mitochondrial dynamics. We recently demonstrated that ectopic HRasG12V promotes mitochondrial fragmentation and tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1). However, the role of Drp1 in the setting of endogenous oncogenic KRas remains unknown. Here, we show that Drp1 is required for KRas-driven anchorage-independent growth in fibroblasts and patient-derived pancreatic cancer cell lines, and it promotes glycolytic flux, in part through the regulation of hexokinase 2 (HK2). Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion. Rare tumors that arise in the absence of Drp1 have restored glycolysis but exhibit defective mitochondrial metabolism. This work demonstrates that Drp1 plays dual roles in KRas-driven tumor growth: supporting both glycolysis and mitochondrial function through independent mechanisms.

Keywords: Drp1; KRas; metabolism; mitochondria; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Dynamins / genetics
  • Dynamins / metabolism*
  • Dynamins / physiology*
  • Gene Expression Regulation, Neoplastic
  • Glycolysis
  • Humans
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Dynamics
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • DNM1L protein, human
  • Dnm1l protein, mouse
  • Dynamins