Cited by 135Pancreatic and Hepatic Oncology ResearchCancer, Hypoxia, and MetabolismCancer, Lipids, and Metabolism

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Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells

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Zhu, Xiphias Ge, Chudnovskiy, Aleksey, Baudrier, Lou, Prizer, Benjamin, Liu, Yuyang, Ostendorf, Benjamin N., Yamaguchi, Norihiro, Arab, Abolfozl, Tavora, Bernardo, Timson, Rebecca, Heissel, Søren, de Stanchina, Elisa, Molina, Henrik, Victora, Gabriel D., Goodarzi, Hani, Birsoy, Kıvanç·2021·Cell Metabolism

DOI 10.1016/j.cmet.2020.10.017PMC PMC7790894

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Abstract

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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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: Zhu, Xiphias Ge
Chudnovskiy, Aleksey
Prizer, Benjamin
Ostendorf, Benjamin N.
Yamaguchi, Norihiro
Tavora, Bernardo
Timson, Rebecca
Heissel, Søren
Molina, Henrik
Victora, Gabriel D.
Goodarzi, Hani
Birsoy, Kıvanç
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2021-01
Volume: 33
Issue: 1
Pages: 211-221.e6
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2020.10.017
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
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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Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells

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