Loss of HLF enables metastasis via cell-collagen interaction in solid cancers

Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conducted an in vivo genome-wide CRISPR-Cas9 screen and identified HLF as a potent suppressor of lung metastasis. While HLF translocation is known as an oncogenic event in leukemia, its role in solid cancers remains unclear. Our study revealed that HLF depletion enhanced ccRCC migration and lung metastasis, whereas HLF overexpression abrogated these effects. This finding extended to multiple solid tumor types. In ccRCC patients, HLF expression was reduced at metastatic sites and associated with epigenetic silencing. HLF levels negatively correlated with migration potential in collagen. Mechanistically, HLF regulated leupaxin expression, affecting the integration of collagen stiffness and the actin cytoskeleton through paxillin, thereby repressing cancer cell migration and lung metastasis. These data indicate that HLF influences lung metastasis through cell-collagen interactions in solid tumors. Overall design: RNA-seq in ccRCC cell line 786-O in both knockout (CRISPR-Cas9 sgCtrl vs sgHLF) and overexpression (lentiviral empty vector vs HLF vector) of HLF. ATAC-seq in a ccRCC primary tumor cell line (786-O-P, from primary tumor) and a metastatic tumor cell line (786-O-LM, from lung metastasis) from 786-O cells following orthotopic injection into the kidney of mice. ChIP-seq in ccRCC cell line 786-O for HA-tagged HLF and input under wild type conditions