Abstract Mechanical forces have long been known to affect the progression of cancer, however exact study of the specific consequences of these forces has been hampered by currently available model systems. Traditional cell culture models often lack the ability to incorporate physiologically relevant mechanical forces, and animal models offer too much complexity to be able to effectively isolate and study the mechanical forces. Organ-on-chip (OOC) technology allows for the integration of human relevant physiological forces in a setting conducive to their study. Here, we explore how the early metastatic spread of colorectal cancer (CRC) can be influenced by physiological mechanical forces. Specifically, we investigated the ability of peristaltic motions, responsible for natural bowel motility, to enhance the invasive capability of colon tumor cells. Our microfluidic OOC model comprises of an epithelial channel and endothelial channel separated by a porous membrane allowing for biological and chemical crosstalk between them. Vacuum channels spanning the length of the structure allow force to applied in a cyclic manner mimicking peristaltic contraction and relaxation. Our OOC model supports the addition of tumor microenvironment (TME) components in a piece-wise manner to better understand how specific factors influence the behavior of tumor cells. Analyzing gene and protein expression levels, we have found that peristaltic-like motions induce changes in the Hippo signaling and epithelial-to-mesenchymal (EMT) pathways resulting in greater invasion of tumor cells into the endothelial compartment as observed by on-chip confocal imaging. Moreover, knock down studies have demonstrated that the response to peristaltic-like stretch is driven through a PIEZO1-mediated mechanism. Furthermore, to increase the physiological relevance of our model, we administered peripheral blood mononuclear cells (PBMCs) to the endothelial channel to simulate aspects of the immune TME. Preliminary studies revealed that the recruitment of PBMCs can be altered by the presence of peristaltic-like stretch. Our findings demonstrate that mechanical forces in the CRC TME can dramatically alter tumor behavior as shown in our CRC-OOC model. Citation Format: Curran A. Shah, Carly R. Strelez, Aaron Schatz, Hannah Jiang, Rachel Perez, Shannon M. Mumenthaler. PIEZO1 driven tumor aggressiveness in an organ-on-chip model of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A009.
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