CRISPR-Cas9 screen identifies oxidative phosphorylation as essential for cancer cell survival at low extracellular pH

Unlike most cell types, many cancer cells survive at low extracellular pH (pHe), a chemical signature of tumors. Genes that facilitate survival under acid stress are therefore potential targets for cancer therapies. We performed a genome-wide CRISPR-Cas9 cell viability screen at physiological and acidic conditions to systematically identify gene knockouts associated with pH-related fitness defects in colorectal cancer cells. Knockouts of genes involved in oxidative phosphorylation (NDUFS1) and iron-sulfur cluster biogenesis (IBA57, NFU1) grew well at physiological pHe, but underwent profound cell death under acidic conditions. We identified several small-molecule inhibitors of mitochondrial metabolism that can kill cancer cells at low pHe only. Xenografts established from NDUFS1(-/-) cells grew considerably slower than their wild-type controls, but growth could be stimulated with systemic bicarbonate therapy that lessens the tumoral acid stress. These findings raise the possibility of therapeutically targetingmitochondrial metabolism in combination with acid stress as a cancer treatment option.

Automated summary

Unlike most cell types, cancer cells can survive in low acid environments. Knocking out genes associated with pH-related fitness defects in colorectal cancer cells can cause cell death under acidic conditions. Researchers have also discovered mitochondrial metabolism inhibitors that can specifically kill cancer cells in a low acid environment. The growth of xenografts established from gene-knockout cells is slower, but can be stimulated with bicarbonate therapy to reduce tumor acid stress.