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AACR Annual Meeting – Carly Strelez, Sujatha Chilakala, Ah Young Yoon, Kimya Ghaffarian, Danielle Hixon, Roy Lau, Jonathan E. Katz, Shannon M. Mumenthaler

April 10

Session PO.TB01.03 – Other Nonclinical Models of Cancer

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

Presenter/Authors
Carly Strelez, Sujatha Chilakala, Ah Young Yoon, Kimya Ghaffarian, Danielle Hixon, Roy Lau, Jonathan E. Katz, Shannon M. Mumenthaler. Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California,, Los Angeles, CA
Disclosures
 C. Strelez: None. S. Chilakala: None. A. Yoon: None. K. Ghaffarian: None. D. Hixon: None. R. Lau: None. J.E. Katz: None. S.M. Mumenthaler: None.
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.

Details

Date:
April 10
Event Category:
Website:
https://www.abstractsonline.com/pp8/#!/9325/presentation/3806

Organizer

AACR
Website:
https://www.aacr.org/

Ellison Institute Insights Forum

The Ellison Institute Insights Forum brings together creative and accomplished thinkers to offer their wisdom on some of the key questions we face in fundamentally understanding and controlling cancer and other complex diseases. Through the Ellison Insights Forum conversations, we will brainstorm solutions for some of the thorniest problems in disease biology, particularly cancer, with equally innovative and transformative ideas.


Next Forum: Thursday, March 11 – Role of Evolution in Cancer Treatment

Last Forum Question: How could applying specific principles of evolution/evolutionary theory (and ecology) across biological and temporal scales of cancer revolutionize treatment strategies, reduce resistance, and improve patient outcomes?

Forum Recording: Click HERE to view the discussion between:

Charles Swanton, MD, PhD – senior group leader of the Cancer Evolution and Genome Instability Laboratory at the Francis Crick Institute, and oncologist at the UCL Cancer Institute

Susan Rosenberg, PhD – Ben F Love Chair in Cancer Research; Professor of Molecular & Human Genetics, Biochemistry & Molecular Biology, and Molecular Virology & Microbiology; and Founder and Leader, Mechanisms in Evolution Program, Dan L Duncan Comprehensive Center, Baylor College of Medicine

Robert Gatenby, MD – Department Chair in Radiology and Co-Director Center of Excellence for Evolution Based Therapy at Moffitt Cancer Center

Kenneth Pienta, MD – Donald S. Coffey Professor of Urology and Professor of Oncology, Pharmacology and Molecular Sciences, and Chemical and Biomolecular Engineering at Johns Hopkins University, ACS Professor and Director of Research for the Brady Urological Institute

Moderated by Anna Barker, PhD, Chief Strategy Officer, Ellison Institute and Distinguished Visiting Fellow in Complex Adaptive Systems, Arizona State University and

David B. Agus, MD, Founding Director & CEO, Ellison Institute and Professor of Medicine & Engineering, USC