Abstract 3190: Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis
Authors: Schab Angela , Lomonosova Elena , Cooper Isaac , Teng Stephanie , Ibitoye Zainab , Wilke Danny , Noia Hollie , Mullen Maggie , Longmore Gregory , Fuh Katherine 
Published: June 2022

Introduction: Ovarian cancer is the leading cause of gynecological cancer-related deaths. The propensity for metastasis is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. Work from our lab has demonstrated that stromal cell expression of the receptor tyrosine kinase Discoidin Domain Receptor 2 (DDR2) promotes ovarian cancer metastasis. One stromal compartment that expresses DDR2 is the mesothelial cell layer that surrounds the organs of the peritoneum - the most common location of ovarian cancer metastasis. Although epithelial in origin, mesothelial cells can adopt mesenchymal properties during metastasis and become active participants in the process. Therefore, we hypothesize that mesothelial cell expression of DDR2 promotes stabilization of a mesenchymal phenotype in mesothelial cells, which facilitates ovarian cancer metastasis.

Methods: Human peritoneal mesothelial cells (HPMCs) were isolated from patient omentum samples. HPMCs were immortalized using lentivirus expressing SV40 large T antigen followed by short hairpin control and DDR2 knockdown transfections. qPCR was used to assess transcription and immunoblotting was used to assess protein expression. ELISAs were completed to observe changes in MMP-2 secretion. C57BL6/J mice are used for in vivo studies.

Results: In vitro we have found that DDR2-expressing human peritoneal mesothelial cells promote tumor cell clearance through the mesothelial cell layer. Further, mesothelial cell DDR2 increases mesenchymal-associated gene transcription and signaling, including the mesenchymal associated transcription factor SNAI1 and collagen 1. Mesothelial cell DDR2 expression also leads to increased secretion of the protease MMP-2, which is known to promote metastasis. To determine whether mesothelial cell DDR2 expression contributes to metastasis, we are creating a mesothelial cell-specific DDR2 knockout mouse and control mouse. To do so, we are breeding WT1CreERT2/+ mice as a mesothelial cell specific driver of Cre recombination with DDR2 floxed mice to knockout DDR2 as a result of Cre recombination, and Ai14 mice as a Cre reporter as they express tdTomato only in the presence of Cre. After validation of the model, syngeneic ovarian cancer cells will be intraperitoneally injected and tumor burden, ECM structure, and signaling changes will be compared between knockout and control mice.

Conclusions: This work will increase our understanding of mesothelial cells’ contribution to metastasis with the possibility of identifying inhibition of DDR2 as a therapeutic target for ovarian cancer patients.

Citation Format: Angela Schab, Elena Lomonosova, Isaac Cooper, Stephanie Teng, Zainab Ibitoye, Danny Wilke, Hollie Noia, Maggie Mullen, Gregory Longmore, Katherine Fuh. Investigating tumor-mesothelial cell interactions during ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3190.