Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
Open accessAbstract
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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PDAC cell lines classified by bioenergetic preferences and response to metabolic inhibitors revealed glycolytic, lipogenic, and slow-proliferating metabolic subtypes.
“PDAC cell lines classified by bioenergetic preferences and response to metabolic inhibitors revealed “glycolytic”, “lipogenic”, and “slow proliferating” metabolic subtypes238”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [238]
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The Landscape of Cancer Metabolism as a Therapeutic Target
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c-Myc/GRPEL1 maintains fatty acid synthesis via FASN to support PDAC cell proliferation
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Reciprocal Dynamics of Metabolism and mRNA Translation in Tumor Angiogenesis
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Targeting metabolism to combat anticancer and antibacterial drug resistance
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- Authors
- Halbrook, C. J., Thurston, G., Boyer, S., Anaraki, C., Jiménez, J. A., McCarthy, A., 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, C., & Lyssiotis, C. A.
- Affiliations
- University of California, Irvine (US)
- University of Michigan (US)
- University of Manchester (GB)
- Henry Ford Health (US)
- University of California, Los Angeles (US)
- Indiana University Health (US)
- Cancer Research UK Scotland Institute (GB)
- University of Pennsylvania (US)
- The University of Texas MD Anderson Cancer Center (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Halbrook, Christopher J.
- Lyssiotis, Costas A.
- ORCID
- Halbrook, Christopher J.
- Anaraki, Cecily
- Jiménez, Jennifer A.
- McCarthy, Amy
- Steele, Nina G.
- Kerk, Samuel A.
- Hong, Hanna S.
- Lin, Lin
- Scipioni, Lorenzo
- Sajjakulnukit, Peter
- Andren, Anthony
- Singh, Rima
- Nelson, Barbara S.
- Van Den Bergh, Fran
- 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.
- Lyssiotis, Costas A.
- Venue
- Nature Cancer
- Published
- 2022-11-21
- Volume
- 3
- Issue
- 11
- Pages
- 1386-1403
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC9701142
- OpenAlex
- W4309666883
- Cited by
- 80
- References
- 61
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 21 · 2023: 13 · 2022: 1
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Funders
- V Foundation for Cancer Research (V2021-026)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (F32CA228328, K99/R00CA241357, P30CA062203, F31CA254079, F31CA247457, R01CA229803, U01CA-224145, R01CA151588, R01CA198074, P30CA046592, R37CA237421, R01CA244931, R01CA248160)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933)
- National Pancreas Foundation Sky Research Foundation
- National Cancer Research Institute (A19258)
- American Association for Cancer Research (17-20-01-LYSS)
- American Cancer Society (RSG-18-186-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, tumor microenvironment, cancer metabolism, GCN2, integrated stress response, tumor heterogeneity, metabolic crosstalk, aspartate biosynthesis, PEG-asparaginase, phenformin, treatment resistance
- MeSH terms
- Adenocarcinoma, Animals, Asparagine, Humans, Pancreatic Neoplasms, Symbiosis, Mice, Tumor Microenvironment
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