Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells Journal Article
| 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. |
| Article Title: | Functional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells |
| Abstract: | Using in vivo CRISPR screens, Zhu et al. map metabolic genes essential for pancreatic cancer cells to grow in culture and as tumors. While most essentialities are similar under these conditions, genetic screens identify heme synthesis and autophagy as metabolic requirements specific to the tumor environment. © 2020 Elsevier Inc. 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. © 2020 Elsevier Inc. |
| Keywords: | controlled study; unclassified drug; cancer growth; nonhuman; cd8+ t lymphocyte; animal cell; mouse; apoptosis; animal experiment; animal model; in vivo study; cancer cell culture; in vitro study; pancreatic cancer; oncogene k ras; cell metabolism; functional genomics; tumor necrosis factor; reduced nicotinamide adenine dinucleotide dehydrogenase; peptides and proteins; heme; tumor escape; cancer metabolism; priority journal; article; clustered regularly interspaced short palindromic repeat; tumor immune evasion; heme synthesis; metabolic phenotype; pancreatic ductal carcinoma cell line; autophagy (cellular); in vivo crispr screen; tapbp protein; transporter associated with antigen processing 1 |
| Journal Title: | Cell Metabolism |
| Volume: | 33 |
| Issue: | 1 |
| ISSN: | 1550-4131 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2021-01-05 |
| Start Page: | 211 |
| End Page: | 221.e6 |
| Language: | English |
| DOI: | 10.1016/j.cmet.2020.10.017 |
| PUBMED: | 33152324 |
| PROVIDER: | scopus |
| PMCID: | PMC7790894 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2021 -- Source: Scopus |
