Cells on the surface of the ovary and the Fallopian tube (epithelial cells) communicate (signal) with each other and the meshwork (extra cellular matrix or ECM) around them to achieve normal growth. Specifically, the cells receive signals and feedback by interactions between adhesion receptors (integrins) and the ECM. These signals may be both mechanical and biochemical in nature and are regulated by growth factors like TGF-ß. As an inherent safety mechanism, the absence of these signals causes cells to rapidly undergo cell death (apoptosis) through a regulated process termed anoikis, thereby ensuring cell survival only when cells are in their physiological environment. Loss of such safety mechanisms promotes disease spread. Several lines of evidence have demonstrated roles for TGF-ß as a regulator of cancer progression through effects on the cancer cells themselves or on the ECM. Previous work has demonstrated frequent loss of expression of the type III TGF-ß receptor (TßRIII/betaglycan) correlating with disease and an overall poorer survival outcome. TßRIII can reduce ovarian cancer cell invasive behavior and regulate cell adhesion via interactions with the adhesion receptor integrin a5ß1. The overall objective is to investigate how loss of TßRIII in ovarian cancer with concomitant increase of TGF-ß in the microenvironment acts as a mechanism, utilized by ovarian cancers to evade cues that normally induce anoikis.
Traditional concepts of metastasis do not apply to ovarian cancer. High Grade Serous Ovarian Cancer (HGSOC) does not have any anatomical barriers to seeding/attaching to the peritoneal cavity to trigger metastasis. Hence, there is an urgent need to identify mechanisms that promote normal cell and tissue behavior in the environment including that in the peritoneal cavity. The proposed work will evaluate the importance of targeting TGF-ß and its pathways in the tumor microenvironment as an adjunct or in combination with other molecular therapeutics and chemotherapy. Greater understanding of the ways in which normal and ovarian cancer cells respond to the environment may provide an array of new strategies for therapeutic development especially since the inherent instability of the genome of HGSOC has in recent years shifted attention to targeting the tumor microenvironment. As such, a portion of this work proposes to directly investigate these avenues. If successful, these preclinical and mechanistic studies would serve as precursors to the design of subtype specific Phase I clinical trials. In the interim, evaluating the contribution of anoikis resistance in ovarian cancer and determining that loss of TßRIII results in reduced response to biomechanical cues and anoikis resistance, would help in evaluating the prognostic relevance of soluble TßRIII (that can bind TGF-ß) as a biomarker for aggression and as a predictor of response to therapies.