Defining the impact of detachment sensing proteins in ovarian cancer metastasis

About This Grant

Ovarian cancer is the most lethal gynecological cancer in the United States with poor survival due to extensive peritoneal metastasis. We discovered a previously uncharacterized early response signature to matrix detachment of high-grade serous adenocarcinoma cells, the most common ovarian cancer histologic subtype. This signature is associated with poor patient outcomes and distinct pro-metastatic signaling nodes. We find that the atypical GTPase RHOV, the most significantly induced gene in this signature, is essential for peritoneal metastasis in vivo, promoting anoikis resistance, invasion and clearance of mesothelial cells, an essential step in peritoneal metastasis. Our data reveals RHOV functions as a novel TGF-β/SMAD signaling integrator in OC, a previously uncharacterized function of this understudied GTPase. This finding represents a critical mechanistic link between early detachment responses and established pro-metastatic signaling pathways in ovarian cancer. Our overall hypothesis is that the rapid induction of the detachment response signature is a crucial step for initiating downstream signaling events necessary for ovarian cancer metastasis. Leveraging the PIs' complementary expertise in ovarian cancer research, we will use innovative approaches including in vivo CRISPR screens, auxin-inducible degradation systems, transcriptomics and imaging strategies in cell lines, xenograft tumors, and patient-derived models. In Aim1 we will identify essential genes within the clinically significant detachment response signature and delineate their convergent signaling pathways using unbiased functional genomics. In Aim 2 we will determine how RHOV and the detachment signature reprograms endocytic trafficking to change cellular signaling as exemplified by the TGF-β pathway and evaluate RHOV expression and the detachment signature as a biomarker for TGF-β inhibitor sensitivity. Defining the essential genes and downstream signaling of the detachment response including the novel RHOV- TGF-β/SMAD axis will identify key adaptations of metastatic ovarian cancer that can be targeted therapeutically. This work shifts the paradigm from studying late-stage adaptations to understanding the earliest events in the metastatic cascade, potentially leading to novel biomarker-guided precision medicine approaches for ovarian cancer patients.