Abstract IA020: Microphysiological systems to decipher tumor-stromal interactions in colorectal cancer

Abstract

Abstract Cancer is a complex adaptive system driven by the intricate interplay between tumor cells and their microenvironment. Among these interactions, cancer-associated fibroblasts (CAFs), the predominant cellular component of the tumor stroma, are frequently linked with an unfavorable prognosis and play an important role in the progression of various cancers. Although extensive literature has underscored the impact of CAFs on cancer cell behaviors such as proliferation and invasion, the stromal influence on phenotypic plasticity in the context of treatment response and metastasis remains largely unexplored. Furthermore, preclinical treatment studies often concentrate on drug-induced changes in tumor cells with little investigation into the impact on surrounding stromal cells. To enhance our comprehension of the intricate and dynamic interactions between cancer cells and their microenvironment, we are utilizing quantitative high-content imaging in conjunction with more physiologically relevant patient-derived model systems, such as organoids and organ-on-chip technologies. Here we will describe our experimental workflows and demonstrate how the incorporation of mathematical modeling enhances our understanding of 3D organoid growth dynamics and facilitates a more detailed examination of drug resistance influenced by tumor plasticity. One illustrative example we will emphasize involves the treatment of CAFs with an anti-epidermal growth factor receptor (EGFR) targeted agent, cetuximab, resulting in an increased secretion of epidermal growth factor (EGF). This heightened EGF secretion was sufficient to render neighboring tumor cells resistant to cetuximab treatment. These efforts aim to increase our understanding of tumor-stromal interactions in cancer evolution, particularly emphasizing the functional and therapeutic potential of CAFs, through the integration of expertise across disciplines. Citation Format: Shannon Mumenthaler. Microphysiological systems to decipher tumor-stromal interactions in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA020.