Background:  The Hippo pathway orchestrates tissue regeneration, tumorigenesis, drug resistance, and metastasis through a kinase cascade that inactivates YAP/TAZ, and has emerged as a pivotal regulator of ovarian cancer. Expression of the core Hippo signaling kinases LATS1 and LATS2 is frequently lost or reduced, which correlates with poor prognosis. In this study, our objective was to explore the consequences of loss of LATS1/2 in ovarian cancer cells.

Methods: The deletion of Lats1/2 was achieved by the intrabursal injection of adenovirus expressing Cre-recombinase in the Lats1/2^fl/fl mice or in vitro treatment of mouse ovarian surface epithelial (mOSE) cells isolated from Lats1/2^fl/fl mice.  Flow cytometry assessed PD-L1 expression in the Lats1/2 knockout mOSE cells. Colony formation and qRT-PCR were performed to determine the effects of LATS1/2 on the features of stemness and the epithelial–mesenchymal transition. RNA-seq analysis was performed on the Lats1/2 knockout mOSE cells and human ovarian cancer cell lines.

Results: Histologically, tumors derived from the conditional deletion of Lats1/2 resembled high-grade serous carcinoma starting from the mOSE and were strongly positive for PAX8, WT1, CK19 and Ki67. Loss of LATS1/2 enhanced the proliferation, sphere formation and invasion ability, upregulated core stemness and mesenchymal marker genes, downregulated epithelial marker genes, and increased PD-L1 expression in the mOSE cells. Analysis of RNA-seq data revealed significant increases in the activity of PI3K-AKT and other signaling pathways involved in cancer.

Conclusions: Loss of LATS1/2 promotes ovarian cancer initiation and progression using multiple mechanisms, including enhanced stemness features, AKT signaling, and PD-L1 expression. Further study will advance our understanding of ovarian cancer immunobiology and inform novel survival-improving therapies, such as treating LATS1/2_low ovarian cancers with the YAP/TAZ-targeting drug verteporfin.