In vivoCRISPR screen definesSlc25a37as an organ-specific regulator of antioxidant metabolism in metastasis

Abstract

SUMMARYMetastasizing cancer cells must adapt their metabolism to the nutrient environment of distant organs. We performed a loss-of-function CRISPR screen against Solute Carrier Transporters (SLCs) in a breast cancer mouse model to define nutrient requirements for lung and liver metastases. Most SLC transporter dependencies of metastases were organ-specific such as the mitochondrial iron importer Slc25a37 (mitoferrin-1, Mfrn1), whose loss inhibited liver but not lung metastasis. Accordingly, SLC25A37 was highly expressed in liver compared to lung metastases of breast cancer patients. Functionally,Slc25a37expression was induced by HIF1α to support heme synthesis. This enabled cancer cells to grow in hypoxic liver regions because they utilized heme to synthesize the lipophilic antioxidant bilirubin. Treating mice with a ferroptosis inhibitor fully restored the capacity ofSlc25a37deficient cancer cells to grow in the liver. Thus, we defined the nutrient transport liabilities of lung and liver metastases and identified Slc25a37-dependent bilirubin synthesis as a requirement of liver metastasis to resist ferroptosis.Abstract Figure