4.8 Article

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

Journal

NATURE METABOLISM
Volume 4, Issue 6, Pages 724-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s42255-022-00583-z

Keywords

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Funding

  1. NIH/National Cancer Institute (NCI) [5370 P30CA16087]
  2. NIH [1K99CA248838-01/4R00CA248838-02, T32 CA009161]
  3. NCI [DP2 OD024174-01]
  4. AACR NextGen grant
  5. Pershing Square Sohn foundation
  6. Breast Cancer Research Foundation
  7. NIH/NCI [CA210263]

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This study reveals that pancreatic tumor cells overcome aspartate limitation in hypoxia by upregulating macropinocytosis.
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. In this work, using a combination of metabolomics and CRISPR-based genetic screens, Garcia-Bermudez, Badgley, Prasad et al. show that pancreatic cancer cells overcome aspartate limitation in hypoxia by upregulating macropinocytosis.

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