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功能基因组学揭示胰腺癌细胞的代谢依赖性
作者:小柯机器人 发布时间:2020/11/6 20:08:49

美国洛克菲勒大学Kvan Birsoy研究组取得一项新突破。他们利用体内功能基因组学揭示了胰腺癌细胞的代谢依赖性。2020年12月4日,《细胞-代谢》杂志在线发表了这项成果。

为了揭示胰腺肿瘤细胞的代谢特点,研究人员在培养或植入免疫功能小鼠的胰腺导管腺癌(PDAC)细胞中进行了以代谢为中心的CRISPR筛选。出乎意料的是尽管在这些条件下大多数代谢基因的必需性相似,但是一小部分代谢基因对于肿瘤的进展是必不可少的。其中,由于体内血红素的作用有限,血红素合成基因的缺失降低了肿瘤的生长,而这种作用与组织来源或免疫系统无关。该筛选还发现自噬是胰腺肿瘤免疫逃逸的代谢需求。

从机制上讲,自噬可通过TNFα诱导的体外细胞死亡保护癌细胞免受CD8+ T细胞的杀伤。总而言之,这些结果揭示了由微环境限制和免疫系统引起的代谢依赖性,从而提供了潜在的抗癌靶标。

据悉,PDAC细胞需要快速的新陈代谢来克服营养限制和免疫监视。然而,对于胰腺肿瘤在体内生长所必需的代谢途径知之甚少。

附:英文原文

Title: Functional Genomics In Vivo Reveal Metabolic Dependencies of Pancreatic Cancer Cells

Author: Xiphias Ge Zhu, Aleksey Chudnovskiy, Lou Baudrier, Benjamin Prizer, Yuyang Liu, Benjamin N. Ostendorf, Norihiro Yamaguchi, Abolfozl Arab, Bernardo Tavora, Rebecca Timson, Sren Heissel, Elisa de Stanchina, Henrik Molina, Gabriel D. Victora, Hani Goodarzi, Kvan Birsoy

Issue&Volume: 2020-11-04

Abstract: Pancreatic ductal adenocarcinoma (PDAC) cells require substantial metabolic rewiringto overcome nutrient limitations and immune surveillance. However, the metabolic pathwaysnecessary for pancreatic tumor growth in vivo are poorly understood. To address this, we performed metabolism-focused CRISPR screensin PDAC cells grown in culture or engrafted in immunocompetent mice. While most metabolicgene essentialities are unexpectedly similar under these conditions, a small fractionof 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 identifyautophagy as a metabolic requirement for pancreatic tumor immune evasion. Mechanistically,autophagy protects cancer cells from CD8+ T cell killing through TNFα-induced celldeath in vitro. Altogether, this resource provides metabolic dependencies arising from microenvironmentallimitations and the immune system, nominating potential anti-cancer targets.

DOI: 10.1016/j.cmet.2020.10.017

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30550-7

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx