Abstract IA25: Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma

Alterations of the Hippo signaling pathway have been found in patients with sarcomatoid renal cell carcinoma, a highly aggressive kidney disease with rapid progression and poor prognosis. It is unclear whether deregulated Hippo pathway is a primary cause of sarcomatoid cancers. To investigate whether conditional (kidney-specific) Hippo knockout leads to renal cancer development and/or sarcomatoid dedifferentiation, we conditionally inactivated both Lats1 and Lats2 from the adult renal proximal tubule epithelial cells. Mosaic deletion of Lats1 and Lats2 in the adult proximal tubules results in cell-autonomous sarcomatoid renal cell carcinoma ((54%) as early as 8 weeks after gene deletion) and lung metastasis. RNA sequencing of tumors compared to control renal cortices revealed massive transcriptional changes, with 2,292 genes significantly upregulated (FC>2) and 2261 genes significantly downregulated (FCE‚0.5). To visualize the cellular onset and progression of renal defects, we conducted histologic examination at different time points after induction of Lats1/2 deletion. Mutant kidneys displayed tubular atrophy with glomerular cysts. Loss of proximal tubule epithelial markers, and de novo expression of the mesenchymal marker vimentin, indicated that kidney epithelial cells had undergone an epithelial-to-mesenchymal transition (EMT). These studies demonstrate that loss of Lats1/2 rapidly leads to aggressive, metastatic sarcomatoid renal cell carcinoma. Citation Format: Antoine Reginensi, Sanjay Jain, Benjamin Humphreys, Jess Shen, Didier Hodzic, Jeff Wrana, Helen McNeill. Adult deletion of Lats1/2 leads to sarcomatoid renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA25.