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Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
Halbrook, C. J. Thurston, G. Boyer, S. Anaraki, C. Jiménez, J. A. McCarthy, Amy Steele, N. G. Kerk, S. A. Hong, H. S. Lin, L.
Halbrook, C. J.
Thurston, G.
Boyer, S.
Anaraki, C.
Jiménez, J. A.
McCarthy, Amy
Steele, N. G.
Kerk, S. A.
Hong, H. S.
Lin, L.
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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.
Authors
Halbrook, C. J.
Thurston, G.
Boyer, S.
Anaraki, C.
Jiménez, J. A.
McCarthy, Amy
Steele, N. G.
Kerk, S. A.
Hong, H. S.
Lin, L.
Law, F. V.
Felton, C.
Scipioni, L.
Sajjakulnukit, P.
Andren, A.
Beutel, A. K.
Singh, R.
Nelson, B. S.
Van Den Bergh, F.
Krall, A. S.
Mullen, P. J.
Zhang, L.
Batra, S.
Morton, J. P.
Stanger, B. Z.
Christofk, H. R.
Digman, M. A.
Beard, D. A.
Viale, A.
Zhang, J.
Crawford, H. C.
Pasca di Magliano, M.
Jorgensen, Claus
Lyssiotis, C. A.
Thurston, G.
Boyer, S.
Anaraki, C.
Jiménez, J. A.
McCarthy, Amy
Steele, N. G.
Kerk, S. A.
Hong, H. S.
Lin, L.
Law, F. V.
Felton, C.
Scipioni, L.
Sajjakulnukit, P.
Andren, A.
Beutel, A. K.
Singh, R.
Nelson, B. S.
Van Den Bergh, F.
Krall, A. S.
Mullen, P. J.
Zhang, L.
Batra, S.
Morton, J. P.
Stanger, B. Z.
Christofk, H. R.
Digman, M. A.
Beard, D. A.
Viale, A.
Zhang, J.
Crawford, H. C.
Pasca di Magliano, M.
Jorgensen, Claus
Lyssiotis, C. A.
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Date
2022
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Article
Citation
Halbrook CJ, Thurston G, Boyer S, Anaraki C, Jiménez JA, McCarthy A, et al. Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells. Nat Cancer. 2022 Nov;3(11):1386-403. PubMed PMID: 36411320. Pubmed Central PMCID: PMC9701142 Therapeutics and T-Knife Therapeutics and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer and targeting the GOT1 pathway as a therapeutic approach (US patent numbers 2015126580-A1 and 05/07/2015; US patent numbers 20190136238 and 05/09/2019; international patent numbers WO2013177426-A2 and 04/23/2015). The remaining authors declare no competing interests. Epub 2022/11/22. eng.