Investigating the Role of Hippo/Warts Signaling in Sarcomatoid Renal Cell Carcinoma

Abstract

Renal cell carcinomas (RCCs) are the most common kidney malignancy and one of the most common cancers overall. Sarcomatoid RCC (sRCC) is a particularly aggressive subtype of RCC which displays a high rate of metastasis and poor prognosis, contributing to a disproportionately high clinical burden. Attempts to identify driver mutations of sarcomatoid transformation have revealed frequent mutations in components of the Hippo/Warts pathway, a highly conserved regulator of genes controlling proliferation and apoptosis which is frequently dysregulated in cancer. Here, I describe the generation and characterization of a GEMM which gives rise to metastatic sRCC: deletion of Hippo pathway kinases Lats1/2 in adult kidney epithelia. Lats1/2 mutant tumors respond to immune checkpoint inhibition (ICI), as is seen in some human sRCCs. Bioinformatic analysis reveals an enrichment of serum response factor (Srf) targets amongst genes upregulated following Lats1/2 deletion. Ablating Srf in the Lats mutant background causes Lats;Srf mutant cells to undergo epithelial to mesenchymal transition but not progress to fulminant tumors in vivo. RNA-sequencing, CyTOF analysis, and implantation studies in immunocompromised mice suggest that Srf drives a pro-tumor microenvironment in Lats1/2 mutant sRCC. Additionally, transcriptional analysis identifies a subset of human RCCs that express an Srf transcriptional signature, indicating that Srf may contribute to the pathogenesis of RCC. This work has elucidated a novel role for Srf in immune modulation with potential implications for the treatment of human RCC