Mitochondrial oxidative transport is inhibited by NDUFA4L2 to promote primary tumor escape [ATAC-Seq]
Metastases cause most cancer deaths and reflect cellular transitions from epithelial to mesenchymal states (EMT) that enable primary tumor escape to seeding and growth at metastatic sites. Rare cancer-driving mutations that disrupt mitochondrial oxidative metabolism (OxPhos) can promote EMT, yet molecular mechanisms that more broadly link metabolism to metastases are uncertain. Analyses of clear cell renal cell carcinoma (RCC) cells identified the hypoxia-induced mitochondrial electron transport inhibitor, NDUFA4L2, as highly enriched in cancer cells with EMT signatures. NDUFA4L2 suppressed OxPhos, altering levels of metabolites that govern chromatin accessibility of EMT-related loci. NDUFA4L2 specifically promoted cell escape from primary orthotopic RCC rather than colonization to drive lung metastasis. These results demonstrate OxPhos inhibition by NDUFA4L2 is essential for RCC cells undergoing EMT to escape primary tumors. Overall design: ATAC-seq of murine renal cell carcinoma cell line (RENCA) with empty vector (EVP), NDUFA4L2 knocked out using CRISPR/CAS9 (KO), and NDUFA4L2 stably re-expressed in the knockout cell line (RES). 3 replicates were sequenced per cell line (except the KO, which only had two replicates).