Genome-wide CRISPR screening identifies critical regulators controlling ccRCC lung metastasis

Clear cell renal cell carcinoma (ccRCC), which accounts for approximately 85% of all renal cancers, is resistant to a variety of cancer therapies and is highly lethal. Metastasis poses a significant challenge in the treatment of kidney cancer, with lung metastasis accounting for approximately 40-50% of all kidney cancer metastases. While the 5-year average survival rate for kidney cancer without metastasis is approximately 90%, the survival rate for distant metastasis (such as lung, bone and brain) is only 10-15%, emphasizing the urgent need to understand the biology underlying kidney cancer lung metastasis. Here we perform a genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screen and identify that Hepatic leukemia factor (HLF) controls lung metastasis in ccRCC. Most of the reports about HLF focused on leukemia studies and its function in solid cancer has never been characterized. This proposal, for the first time, will characterize the role of HLF in ccRCC lung metastasis and examine its underlying molecular mechanism. In Specific Aim 1, we will characterize the functional significance of HLF on kidney cancer lung metastasis by using gain-of-fuction and loss-of-fucntion studies in ccRCC orthotopic xenograft tumors, patient derived xenograft (PDX) models, immune- competent mouse models and humanized mouse models. In Specific Aim 2, we will delineate the molecular mechanism by which HLF loss promotes kidney cancer lung metastasis by integrated ChIP-Seq and RNA-Seq analysis. In particular, we will delineate the molecular mechanism of HLF-LPXN on regulating ccRCC migration at the single cell level. Successful completion of these aims will provide mechanistic insight into signaling pathways controlling lung metastasis in ccRCC and set the foundation for therapeutic intervention targeting the HLF signaling axis in ccRCC.