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Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) cells require substantial metabolic rewiring to overcome nutrient limitations and immune surveillance. However, the metabolic pathways necessary for pancreatic tumor growth in vivo are poorly understood. To address this, we performed metabolism-focused CRISPR screens in PDAC cells grown in culture or engrafted in immunocompetent mice. While most metabolic gene essentialities are unexpectedly similar under these conditions, a small fraction of metabolic genes are differentially required for tumor progression. Among these, loss of heme synthesis reduces tumor growth due to a limiting role of heme in vivo, an effect independent of tissue origin or immune system. Our screens also identify autophagy as a metabolic requirement for pancreatic tumor immune evasion. Mechanistically, autophagy protects cancer cells from CD8+ T cell killing through TNFα-induced cell death in vitro. Altogether, this resource provides metabolic dependencies arising from microenvironmental limitations and the immune system, nominating potential anti-cancer targets.
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“MHC-I expression is low at the PDAC cell surface, instead found predominantly localized within autophagosomes and lysosomes227”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [227]
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Metadata
- Authors
- Zhu, X. G., Chudnovskiy, A., Baudrier, L., Prizer, B., Liu, Y., Ostendorf, B. N., Yamaguchi, N., Arab, A., Tavora, B., Timson, R., Heissel, S., de Stanchina, E., Molina, H., Victora, G. D., Goodarzi, H., & Birsoy, K.
- Affiliations
- Rockefeller University (US)
- University of California, San Francisco (US)
- Corresponding author
- Birsoy, Kıvanç
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 33
- Issue
- 1
- Pages
- 211-221.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7790894
- OpenAlex
- W3095207864
- Cited by
- 130
- References
- 49
- Citations by year
- 2026: 22 · 2025: 19 · 2024: 33 · 2023: 14 · 2022: 28 · 2021: 14
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pershing Square Foundation
- American Association for Cancer Research
- National Institutes of Health
- Robertson Foundation
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, cancer metabolism, metabolic dependencies, heme biosynthesis, autophagy, tumor immune evasion, CRISPR screen, tumor microenvironment, anticancer drug targets
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Experimental, Pancreatic Neoplasms, Mice, Inbred NOD, Mice, Knockout, Carcinoma, Pancreatic Ductal, Cell Proliferation, Mice, CRISPR-Cas Systems
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