Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

Christopher J. Halbrook(Chapman University), Galloway Thurston(University of Michigan), Seth Boyer(University of Michigan), Cecily Anaraki(University of California, Irvine), Jennifer A. Jiménez(University of Michigan), Amy McCarthy(University of Manchester), Nina G. Steele(Henry Ford Health System), Samuel A. Kerk(University of Michigan), Hanna S. Hong(University of Michigan), Lin Lin(University of Michigan), Fiona V. Law(University of California, Irvine), Catherine Felton(University of Manchester), Lorenzo Scipioni(University of California, Irvine), Peter Sajjakulnukit(University of Michigan), Anthony Andren(University of Michigan), Alica K. Beutel(University of California, Irvine), Rima Singh(University of California, Irvine), Barbara Scott Nelson(University of Michigan), Françoise Van den Bergh(University of Michigan), Abigail S. Krall(University of California, Los Angeles), Peter J. Mullen(University of California, Los Angeles), Li Zhang(University of Michigan), Sandeep Batra(Indiana University Health), Jennifer P. Morton(Cancer Research UK Scotland Institute), Ben Z. Stanger(University of Pennsylvania), Heather R. Christofk(University of California, Los Angeles), Michelle A. Digman(University of California, Irvine), Daniel Beard(University of Michigan), Andrea Viale(The University of Texas MD Anderson Cancer Center), Ji Zhang(Indiana University School of Medicine), Howard C. Crawford(Henry Ford Health System), Marina Pasca di Magliano(University of Michigan), Claus Jørgensen(University of Manchester), Costas A. Lyssiotis(University of Michigan)
Nature Cancer
November 21, 2022
10.1038/s43018-022-00463-1
Cited by 73Open Access
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Abstract

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

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