Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia

Javier Garcia-Bermudez, Michael A. Badgley, Sheela Prasad, Lou Baudrier, Yuyang Liu, Konnor La, Mariluz Soula, Robert T. Williams, Norihiro Yamaguchi, Rosa F. Hwang, Laura J. Taylor, Elisa de Stanchina, Bety Rostandy, Hanan Alwaseem, Henrik Molina, Dafna Bar-Sagi, Kıvanç Birsoy

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Stress-adaptive mechanisms enable tumour cells to overcome metabolic constraints under nutrient and oxygen shortage. Aspartate is an endogenous metabolic limitation under hypoxic conditions, but the nature of the adaptive mechanisms that contribute to aspartate availability and hypoxic tumour growth are poorly understood. Here we identify GOT2-catalysed mitochondrial aspartate synthesis as an essential metabolic dependency for the proliferation of pancreatic tumour cells under hypoxic culture conditions. In contrast, GOT2-catalysed aspartate synthesis is dispensable for pancreatic tumour formation in vivo. The dependence of pancreatic tumour cells on aspartate synthesis is bypassed in part by a hypoxia-induced potentiation of extracellular protein scavenging via macropinocytosis. This effect is mutant KRAS dependent, and is mediated by hypoxia-inducible factor 1 (HIF1A) and its canonical target carbonic anhydrase-9 (CA9). Our findings reveal high plasticity of aspartate metabolism and define an adaptive regulatory role for macropinocytosis by which mutant KRAS tumours can overcome nutrient deprivation under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)724-738
Number of pages15
JournalNature Metabolism
Volume4
Issue number6
DOIs
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

Fingerprint

Dive into the research topics of 'Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia'. Together they form a unique fingerprint.

Cite this