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Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells.
Halbrook, Christopher J; Thurston, Galloway; Boyer, Seth; Anaraki, Cecily; Jiménez, Jennifer A; McCarthy, Amy; Steele, Nina G; Kerk, Samuel A; Hong, Hanna S; Lin, Lin; Law, Fiona V; Felton, Catherine; Scipioni, Lorenzo; Sajjakulnukit, Peter; Andren, Anthony; Beutel, Alica K; Singh, Rima; Nelson, Barbara S; Van Den Bergh, Fran; Krall, Abigail S; Mullen, Peter J; Zhang, Li; Batra, Sandeep; Morton, Jennifer P; Stanger, Ben Z; Christofk, Heather R; Digman, Michelle A; Beard, Daniel A; Viale, Andrea; Zhang, Ji; Crawford, Howard C; Pasca di Magliano, Marina; Jorgensen, Claus; Lyssiotis, Costas A.
Affiliation
  • Halbrook CJ; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.
  • Thurston G; University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA. chris.halbrook@uci.edu.
  • Boyer S; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. chris.halbrook@uci.edu.
  • Anaraki C; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA. chris.halbrook@uci.edu.
  • Jiménez JA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • McCarthy A; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Steele NG; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • Kerk SA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Hong HS; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • Lin L; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • Law FV; Department of Surgery, Henry Ford Health System, Detroit, MI, USA.
  • Felton C; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Scipioni L; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Sajjakulnukit P; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Andren A; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • Beutel AK; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • Singh R; Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
  • Nelson BS; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Van Den Bergh F; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Krall AS; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • Mullen PJ; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • Zhang L; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Batra S; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Morton JP; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • Stanger BZ; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • Christofk HR; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Digman MA; Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
  • Beard DA; Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • Viale A; Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zhang J; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.
  • Crawford HC; Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
  • Pasca di Magliano M; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • Jorgensen C; Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lyssiotis CA; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Nat Cancer ; 3(11): 1386-1403, 2022 11.
Article in En | MEDLINE | ID: mdl-36411320
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Adenocarcinoma Limits: Animals / Humans Language: En Journal: Nat Cancer Year: 2022 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Adenocarcinoma Limits: Animals / Humans Language: En Journal: Nat Cancer Year: 2022 Document type: Article Affiliation country: Estados Unidos