Regulation of ovarian cancer metastasis by microenvironment-induced chromatin accessibility and c-Jun activation.

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

A central problem in ovarian cancer (OC) is extensive transcoelomic metastasis. Most patients are diagnosed with disseminated disease, which eventually results in their death from complications, including bowel obstructions, caused by widespread intraperitoneal tumors. Even though most patients are being treated for metastatic disease, no FDA-approved drug is available to specifically target intraperitoneal metastasis. Therefore, it is important to develop new strategies to effectively treat metastasis. A better understanding of the productive reciprocal interactions between metastasizing OC cells and their microenvironment and its mechanism of regulation of metastatic colonization will help identify relevant targets for therapy. We have recapitulated the early events on metastatic colonization using an organotypic 3D culture model mimicking the surface layers of the human omentum and combined that approach with endpoint analysis of matched primary tumors and metastasis from OC patients. Using this approach, we identified a novel phenomenon of microenvironment induced changes in chromatin accessibility that exposes binding sites of the transcription factor c-Jun. We also found that c-Jun is itself regulated by microenvironmental signals in early as well as advanced OC metastasis. Knockout and overexpression experiments demonstrated the importance of c-Jun and its novel direct targets (USP35, SUPT5H, and AKT2) in OC metastasis. The central hypothesis of this proposal is that microenvironmental signals help OC metastasis by activating the transcription factor c-Jun in OC cells, while simultaneously exposing new binding sites in regulatory regions of c-Jun target genes, to increase their transcription, which is necessary for metastatic colonization. Aim 1 will determine the mechanism by which the microenvironmental signals activate c-Jun in the OC cells and cause changes in chromatin accessibility. Aim 2 will identify the mechanism of regulation of OC metastasis by the pleotropic effects of c-Jun and its targets. Transcription factors have traditionally been considered difficult to target clinically. However, targeting upstream regulators or downstream effectors is a viable alternative. This will be tested using OC patient derived xenografts. Successful completion of the proposed research will provide novel insights into the clinically relevant cancer cell- microenvironment crosstalk and how that regulates early and advanced OC metastasis through the combined effects of activation of a transcription factor and induction of chromatin accessibility at its binding sites in promoters of its target genes. Since OC patients present with numerous peritoneal metastases ranging from micro-metastasis to large tumors, this approach will potentially identify an effective therapy for these patients who suffer due to complications caused by the extensive peritoneal dissemination.