Abstract 3833: The role of chemotherapy-induced fibrosis in the maintenance of tumor initiating cells

Abstract

Abstract Around 80 percent of high-grade serous ovarian cancer patients will relapse with chemotherapy resistant disease. Despite extensive research and developments in immunotherapy, there are limited improvements in overall survival for these patients. Recent research has found that the tumor microenvironment (TME) plays a crucial role in tumor initiation, therapy resistance, and tumor relapse. The TME, which consists of immune cells, blood vessels, and an extracellular matrix (ECM) built primarily by fibroblasts, may enhance the survival and growth of tumor-initiating cells (TICs), chemoresistant stem-like cells thought to be responsible for tumor relapse. Cytotoxic chemotherapies have been shown to modify the TME and this modulation may favor the survival of TICs. For example, carboplatin can activate stromal cells such as fibroblasts to secrete an altered ECM profile, including increases in collagen 1a1 and fibronectin production, which can bind specific integrins upregulated in TICs. Using ex-vivo decellularized peritoneum tissues from mice exposed to chemotherapy or vehicle treatment, we observed a 2-fold increase in growth in peritoneums pre-exposed to chemotherapy relative to those pre-exposed to vehicle. We hypothesize that alterations in the ECM following chemotherapy treatment permit TIC adhesion and growth. To investigate this, mouse embryonic fibroblasts (3T3s) were exposed to chemotherapy during ECM production, decellularized, and reseeded with a panel of ovarian cancer cell lines. Our results suggest a significant increase in cell survival in matrices pre-exposed to chemotherapy compared to control matrices pre-exposed to vehicle. Using this model, we are examining the features of cells that preferentially survive on these matrices. In addition to drug resistance, we are using flow cytometry to assess TIC markers, such as CD117, and CD133, and qRT-PCR to measure stemness genes such as SOX2, OCT4, and NANOG. These studies highlight the need for further investigation into the systemic effects of chemotherapies on the TME and how these changes may be fostering cancer cell adhesion, growth, and survival. Understanding these mechanisms will allow us to develop therapies to achieve better clinical outcomes. Citation Format: Omar Lujano-Olazaba, Mikella Robinson, Samuel F. Gilbert, Emily Kogan, Carrie D. House. The role of chemotherapy-induced fibrosis in the maintenance of tumor initiating cells [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 3833.