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.Copyright © 2020 Elsevier Inc. All rights reserved.
About The Expert
Xiphias Ge Zhu
Aleksey Chudnovskiy
Lou Baudrier
Benjamin Prizer
Yuyang Liu
Benjamin N Ostendorf
Norihiro Yamaguchi
Abolfozl Arab
Bernardo Tavora
Rebecca Timson
Søren Heissel
Elisa de Stanchina
Henrik Molina
Gabriel D Victora
Hani Goodarzi
Kıvanç Birsoy
References
PubMed