Loss of Chromosome 8p Governs Tumor Progression and Drug Response by Altering Lipid Metabolism

Publication date: 9 May 2016
Source:Cancer Cell, Volume 29, Issue 5
Author(s): Yanyan Cai, Jonathan Crowther, Tibor Pastor, Layka Abbasi Asbagh, Maria Francesca Baietti, Magdalena De Troyer, Iria Vazquez, Ali Talebi, Fabrizio Renzi, Jonas Dehairs, Johannes V. Swinnen, Anna A. Sablina
Large-scale heterozygous deletions are a hallmark of cancer genomes. The concomitant loss of multiple genes creates vulnerabilities that are impossible to reveal through the study of individual genes. To delineate the functional outcome of chromosome 8p loss of heterozygosity (LOH), a common aberration in breast cancer, we modeled 8p LOH using TALEN-based genomic engineering. 8p LOH alters fatty acid and ceramide metabolism. The shift in lipid metabolism triggers invasiveness and confers tumor growth under stress conditions due to increased autophagy. The resistance of 8p-deleted cells to chemotherapeutic drugs concurs with poorer survival rates of breast cancer patients harboring an 8p LOH. The autophagy dependency of 8p-deleted cells provides the rational basis for treatment of 8p LOH tumors with autophagy inhibitors.

Graphical abstract

Teaser

Cai et al. examine the effect of chromosome 8p deletion, which is common in carcinomas. While 8p loss is insufficient to transform cells, it alters fatty acid and ceramide metabolism, leading to increased invasiveness and enhanced autophagy that allow tumors to grow under stress conditions.


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