2. Academic Validation
  3. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

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

  • Nat Cancer. 2022 Nov 21. doi: 10.1038/s43018-022-00463-1.
Christopher J Halbrook 1 2 3 1,  Galloway Thurston 4,  Seth Boyer 4,  Cecily Anaraki 5,  Jennifer A Jiménez 4,  Amy McCarthy 6,  Nina G Steele 7 8,  Samuel A Kerk 4,  Hanna S Hong 4,  Lin Lin 4,  Fiona V Law 5,  Catherine Felton 6,  Lorenzo Scipioni 9,  Peter Sajjakulnukit 4,  Anthony Andren 4,  Alica K Beutel 5,  Rima Singh 5,  Barbara S Nelson 4,  Fran Van Den Bergh 4,  Abigail S Krall 10,  Peter J Mullen 10,  Li Zhang 4,  Sandeep Batra 11,  Jennifer P Morton 12,  Ben Z Stanger 13,  Heather R Christofk 10,  Michelle A Digman 9,  Daniel A Beard 4,  Andrea Viale 14,  Ji Zhang 15,  Howard C Crawford 4 8,  Marina Pasca di Magliano 7 16,  Claus Jorgensen 6,  Costas A Lyssiotis 17 18 19
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.
  • 2 University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA. chris.halbrook@uci.edu.
  • 3 Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. chris.halbrook@uci.edu.
  • 4 Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • 6 Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • 7 Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 8 Department of Surgery, Henry Ford Health System, Detroit, MI, USA.
  • 9 Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
  • 10 Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • 11 Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
  • 12 Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 13 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 14 Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 15 Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 16 University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 17 Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
  • 18 University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
  • 19 Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
PMID: 36411320 DOI: 10.1038/s43018-022-00463-1
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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