Abstract A34: Induction of a novel ETS1/FAK pathway in metastasizing ovarian cancer cells by the omental microenvironment primes them for metastatic colonization

Abstract

Metastatic colonization of ovarian cancer involves productive paracrine/juxtacrine interactions with the microenvironment. The resulting induction of an adaptive response in the cancer cells enables them to establish themselves in the new microenvironment and take advantage of the new factors available. A key feature of this adaptation is induced changes in gene expression through transcriptional regulation as a result of microenvironmental cues. However, the identities of transcription factors induced by the metastatic microenvironment in ovarian cancer and their mechanism of action are poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1, a member of the ETS family of TFs, as an essential driver of metastatic colonization. Increased ETS1 expression was induced in metastasizing ovarian cancer cells interacting with the mesothelial cells covering the surface of the omentum. The mechanism of upregulation was through the activation of p44/42 MAP kinase signaling in the cancer cells induced by TGFbeta from the microenvironment. We also found an increased ETS1 expression in human ovarian cancer samples as compared to normal fallopian tubes using a tissue microarray. Moreover, higher expression of ETS1 was a predictor of poor prognosis in ovarian cancer patients. Knocking down ETS1 decreased migration, proliferation, and colony formation as well as invasion through and colonization of the organotypic 3D culture. Overexpression of ETS1 had the opposite effect. CRISPR/Cas9-mediated knockout of ETS1 resulted in decreased tumor burden in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis revealed that ETS1 promoted an EMT phenotype and FAK was identified as a novel transcriptional target. Inhibition of FAK functionally mimicked the effects of ETS1 inhibition in the ovarian cancer cells. Moreover, functional rescue experiments established FAK as a downstream effector of ETS1 during ovarian cancer metastasis. Taken together, our results indicate that ETS1 is an essential transcription factor induced in ovarian cancer cells by the microenvironment, which promotes metastatic colonization. This is the first report establishing FAK as a transcriptional target and functional effector of ETS1 in establishing metastatic tumors. Citation Format: Sunil Tomar, Joshua P. Plotnik, James Haley, Joshua Scantland, Zahir Sheikh, Robert Emerson, Dean Lenz, Peter C. Hollenhorst, Anirban K. Mitra. Induction of a novel ETS1/FAK pathway in metastasizing ovarian cancer cells by the omental microenvironment primes them for metastatic colonization. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A34.