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

•Using TALEN technology, we generated a clinically relevant model of 8p deletion•Despite common 8p deletion in cancer, 8p loss does not trigger cell transformation•Loss of 8p alters fatty acid and ceramide metabolism•8p loss confers cell growth under hypoxic conditions due to increased autophagy

SummaryLarge-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.

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