Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer

Abstract

Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33–mega–base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion. Using this isogenic model system, we delineated the functional consequences of chr8p loss and its impact on metastatic behavior and patient survival. We found that metastasis-associated genes on chr8p act in concert to induce an aggressive and invasive phenotype characteristic for chr8p-deleted tumors. Genome-wide CRISPR-Cas9 viability screening in isogenic chr8p-deleted cells served as a powerful tool to find previously unidentified synthetic lethal targets and vulnerabilities accompanying patient-specific chromosomal alterations. Using this target identification strategy, we showed that chr8p deletion sensitizes tumor cells to targeting of the reactive oxygen sanitizing enzyme Nudix hydrolase 17. Thus, chromosomal engineering allowed for the identification of novel synthetic lethalities specific to chr8p loss of heterozygosity.

Selection forces underlying aneuploidy patterns in cancer

“…However, the simultaneous overexpression of a combination of four genes led to a migratory capacity comparable to their overexpression in euploid wildtype cells. 12 These findings suggest that multiple genes contribute to the selection of aneuploid chromosomes in cancer.…”

“… 50 In another study, liver cancer cell lines engineered with monosomy for chromosome arm 8p had accelerated migratory and invasive potential. 12 Finally, Bosco and colleagues showed that the engineered loss of chromosome 18q, which occurs frequently in colorectal cancer, reduced the sensitivity to growth-inhibition by TGF-β. 9 These bottom-up approaches highlight the complexity of the role of aneuploidies in cancer progression.…”

“…A recent study identified deletion of the reactive oxygen sensing enzyme NUDT17 as synthetic lethal with an engineered chromosome 8p deletion cell line. 12 Finally, one limitation for targeting aneuploidy patterns instead of gene mutations could be the relatively easy reversal of the targeted aneuploid chromosome to euploid levels in cancer cells. Changing the copy number of one chromosome can be achieved through a mis-segregation event during cell division which is very likely to occur in cancer cells.…”