Abstract 2989: Peristalsis-like deformations influence tumor cell intravasation and metabolic reprogramming in a novel colorectal cancer-on-chip model

Abstract

Abstract Colorectal cancer (CRC) is one of the deadliest cancers in the U.S., yet we still understand very little about the mechanisms behind this disease. Therefore, we are developing a CRC-Chip model that recapitulates the complex nature of cancer progression in order to increase our understanding of CRC and accelerate the discovery of new treatments. The organ-on-chip technology developed by Emulate, Inc. maintains physiologically relevant aspects of organ structure and function by incorporating tissue compartments and mechanical forces to mimic in vivo peristalsis and fluid flow. The CRC-Chip consists of two microfluidic compartments separated by a porous membrane, with endothelial cells in the bottom channel and normal colon epithelial cells plus fluorescently-labeled CRC cell lines in the top channel. Via confocal microscopy, We observed monitored cancer cells intravasating from the epithelial compartment into the blood vessel compartment via confocal microscopy, mimicking early metastatic spread. A unique advantage of this system is the ability to interrogate how mechanical forces influence cancer cell intravasation. The presence of peristalsis-like deformations increased the invasion rate of cancer cells. To further investigate the increased aggressiveness, viable tumor cells were collected from the effluent of the blood vessel channel reservoir. These shedded circulating cells, representing the invaded CRC cells, showed markers of epithelial to mesenchymal transition (EMT) induction and changes in adhesive properties. To further understand how peristalsis influences CRC cells, we performed mass-spectrometry based metabolomics on the effluent from the top and bottom channels of CRC-chips in the presence or absence of peristalsis-like motions. The differentially expressed metabolites, when mapped with Ingenuity Pathway Analysis, indicated changes primarily to amino acid/central carbon metabolism in the epithelial channel and differential lipid profiles in the endothelial channel when peristalsis was present. Given a majority of CRC metastases occur in the liver, we optimized the coupling of our CRC-Chip with a normal Liver-Chip model to better understand how intravasated tumor cells from a peristaltic colon environment colonize a healthy liver. This work illuminates the important role of mechanical forces in CRC progression, a currently understudied aspect of the tumor microenvironment. Further insights into a better understanding of how peristalsis increases the metastatic spread of CRC cells may lead to the discovery of novel therapeutic strategies that can halt critical steps in tumor progression. Citation Format: Carly Strelez, Sujatha Chilakala, Ah Young Yoon, Kimya Ghaffarian, Danielle Hixon, Roy Lau, Jonathan E. Katz, Shannon M. Mumenthaler. Peristalsis-like deformations influence tumor cell intravasation and metabolic reprogramming in a novel colorectal cancer-on-chip model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2989.