Large-scale heterozygous deletions are a hallmark of cancer genome. Although with high recurrent frequency, the large-scale chromosomal deletions are less explored. Loss of heterozygosity (LOH) of nearly the whole short arm of chromosome 8 (8p) is one of the most common copy number alterations observed in all types of human epithelial cancer. Recent study suggested that co-suppression of multiple 8p genes can synergistically promote tumor growth in mice. On the other hand, 8p locus contains both STOP genes, which are negative regulators of cell growth, and GO genes, which are essential genes or positive regulators of cell growth, suggesting that the consequence of the deletion could depend on the balance of STOP and GO genes. Therefore, the concomitant loss of multiple genes may create vulnerabilities distinct from those arose from losses of single genes that are impossible to reveal through the study of individual genes. The development of genomic editing tools provides us the possibility to model cancer-associated chromosomal deletions. To mimic 8p loss of heterozygosity (LOH) observed in human breast cancers, we generated human mammary cell models harboring targeted 8p LOHs using TALENs-based genomic engineering. Although the 8p chromosomal region contains multiple genes with tumor suppressive properties, loss of 8p did not induce tumorigenic transformation, strongly indicating that large-scale chromosomal deletions should be considered as distinct mutational events. In contrast, 8p LOH resulted in dysregulation of multiple genes involved in lipid metabolism. In concordance with deregulation of gene expression, we found that fatty acid and ceramide metabolism was significantly altered in 8p LOH cells. An increase in fatty acid derivatives triggered enhanced invasiveness and intravasation of 8p-deleted cells. On the other hand, the accumulation of ceramides resulted in increased pro-survival autophagy levels, which conferred tumor growth under stress conditions. The autophagy dependency of 8p-deleted cells provided the rational basis for treatment of 8p LOH tumors with autophagy inhibitors. Our results demonstrate that the experimental models mimicking cancer-associated chromosomal abnormalities provide a powerful system for the functional annotation of the cancer genome, and represent a useful platform to identify drugs that selectively kill tumor cells harboring a particular chromosomal abnormality.