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

Sarbajeet Nagdas, Jennifer A. Kashatus, Aldo Nascimento, Syed S. Hussain, Riley E. Trainor, Sarah R. Pollock, Sara J. Adair, Alex D. Michaels, Hiromi Sesaki, Edward B. Stelow, Todd W. Bauer, David F. Kashatus

Research output: Contribution to journalArticle

Abstract

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. Nagdas et al. find that the mitochondrial fission GTPase Drp1 is required for KRas-driven transformation and pancreatic tumor growth. The inhibition of Drp1 in cells expressing oncogenic KRas leads to impaired glycolytic flux and the eventual loss of mitochondrial metabolic function.

Original languageEnglish (US)
Pages (from-to)1845-1859.e5
JournalCell Reports
Volume28
Issue number7
DOIs
StatePublished - Aug 13 2019

Fingerprint

Dynamins
Tumors
Growth
Mitochondrial Dynamics
Neoplasms
Proteins
GTP Phosphohydrolases
Glycolysis
Pancreatic Neoplasms
Cells
Fluxes
Phosphorylation
Mitochondria
Hexokinase
Fibroblasts
Metabolism
Homeostasis
Fusion reactions
Cell Line

Keywords

  • Drp1
  • KRas
  • metabolism
  • mitochondria
  • pancreatic cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nagdas, S., Kashatus, J. A., Nascimento, A., Hussain, S. S., Trainor, R. E., Pollock, S. R., ... Kashatus, D. F. (2019). Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. Cell Reports, 28(7), 1845-1859.e5. https://doi.org/10.1016/j.celrep.2019.07.031

Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. / Nagdas, Sarbajeet; Kashatus, Jennifer A.; Nascimento, Aldo; Hussain, Syed S.; Trainor, Riley E.; Pollock, Sarah R.; Adair, Sara J.; Michaels, Alex D.; Sesaki, Hiromi; Stelow, Edward B.; Bauer, Todd W.; Kashatus, David F.

In: Cell Reports, Vol. 28, No. 7, 13.08.2019, p. 1845-1859.e5.

Research output: Contribution to journalArticle

Nagdas, S, Kashatus, JA, Nascimento, A, Hussain, SS, Trainor, RE, Pollock, SR, Adair, SJ, Michaels, AD, Sesaki, H, Stelow, EB, Bauer, TW & Kashatus, DF 2019, 'Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth', Cell Reports, vol. 28, no. 7, pp. 1845-1859.e5. https://doi.org/10.1016/j.celrep.2019.07.031
Nagdas S, Kashatus JA, Nascimento A, Hussain SS, Trainor RE, Pollock SR et al. Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. Cell Reports. 2019 Aug 13;28(7):1845-1859.e5. https://doi.org/10.1016/j.celrep.2019.07.031
Nagdas, Sarbajeet ; Kashatus, Jennifer A. ; Nascimento, Aldo ; Hussain, Syed S. ; Trainor, Riley E. ; Pollock, Sarah R. ; Adair, Sara J. ; Michaels, Alex D. ; Sesaki, Hiromi ; Stelow, Edward B. ; Bauer, Todd W. ; Kashatus, David F. / Drp1 Promotes KRas-Driven Metabolic Changes to Drive Pancreatic Tumor Growth. In: Cell Reports. 2019 ; Vol. 28, No. 7. pp. 1845-1859.e5.
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