Abstract B037: Mesothelial cell and ovarian cancer cell cross-talk: Roles of STAT3 and NF-kappaB during mesothelial clearance. [R

Abstract

Abstract Ovarian cancer metastasis remains a major issue for ovarian cancer patients. Therefore, it is important to understand the molecular events that occur during ovarian cancer metastasis. Ovarian cancer can metastasize through a distinct mechanism where cancer cells leave the primary tumor to float in the ascites. Cells in the ascites then attach to and push away the protective barrier of mesothelial cells to invade the underlying tissue and metastasize to other organs. Understanding the key signaling pathways in ovarian cancer cells during mesothelial clearance is important. Additionally, understanding the effects that the ovarian cancer cells have on the mesothelial cells is equally important. To understand what signaling pathways are important for ovarian cancer metastasis, we first analyzed signaling pathways activated in 3D grown ovarian spheroids. We found that the Signal Transducers and Activators of Transcription (STAT)3 pathway was enhanced in these spheroids. The reduction of STAT3 expression by siRNA reduced the ability of OVCAR8 and Heya8 ovarian cancer spheroids to clear the mesothelial cells. This suggests that STAT3 plays an important role in ovarian cancer cells during mesothelial clearance. To better understand the interaction between ovarian spheroids and mesothelial cells, we magnetically separated the two cell types during active mesothelial clearance. Analysis of gene expression demonstrated an increase in STAT3 activity in ovarian spheroids undergoing mesothelial clearance. Surprisingly, STAT3 target genes were not elevated in the mesothelial cells at the same time; however, NF-kappaB target genes were upregulated. Importantly, we found that the NF-kappaB target gene IL-6, which can promote STAT3 activation, was upregulated in the mesothelial cells while the ovarian cancer cells were undergoing clearance. This raised the possibility that the ovarian cancer cells were activating NF-kappaB in the mesothelial cells to express and secrete IL-6 to enhance STAT3 activity in the ovarian cancer cells. Importantly, we have found that conditioned media from ovarian spheroids activated NF-kappaB in the mesothelial cells. In addition, pretreatment with a NF-kappaB inhibitor reduced the ability of ovarian spheroids to clear mesothelial cells. This suggests that there is cross-talk between the two cell types to promote mesothelial clearance. To better understand if this cross-talk occurs between other cells that undergo mesothelial clearance or if this is unique to ovarian cancer, we are in the process of analyzing the interaction of endometriosis cells with mesothelial cells while they undergo mesothelial clearance. We have found that 3D growing endometriosis cells have enhanced STAT3 activation, similar to what we have seen for ovarian cancer, and we are currently assessing the effects of endometriosis cells on NF-kappaB activity in mesothelial cells. Taken together, our results suggest the possibility of targeting both STAT3 and NF-kappaB as a treatment strategy for metastatic ovarian cancer and potentially endometriosis. Citation Format: Allison A. Kloeckner, David F. Walker, Sarah R. Walker. Mesothelial cell and ovarian cancer cell cross-talk: Roles of STAT3 and NF-kappaB during mesothelial clearance. [R [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B037.