Loss of LATS1 and LATS2 promotes ovarian tumor formation by enhancing AKT activity and PD-L1 expression

High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and ultimately resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion and stemness and epithelial–mesenchymal transition (EMT) characteristics. Knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets. Overall design: We report the analysis of RNA sequencing aimed at understanding the effects of Lats1/2 knockout in ovarian surface epithelial (OSE) cells. LATS1/2 are the core kinases of the Hippo signaling pathway, which plays a critical role in regulating cell proliferation and differentiation. Specifically, we performed RNA-seq seven days after OSE cells were transduced with Ad-Cre-GFP or Ad-GFP to investigate the transcriptional consequences of Lats1/2 deletion. The study aims to elucidate the impact of Lats1/2 loss on gene expression profiles, providing insights into its role in ovarian cancer initiation and progression.