Cancer-Associated Fibroblasts Regulate Vascular Growth via Biomechanical Forces

Date: 
02/18/2019 - 3:00pm
Speaker: 
Mary Kathryn Sewell-Loftin, Ph.D., Postdoctoral Fellow, Department of Internal Medicine, Division of Oncology, Washington University in St. Louis
Location: 
Communicore, C1-17


Nearly 1.5 million people will be diagnosed with some form of cancer over the next year. While early detection and treatment strategies have seen rapid improvement over the last few decades, there is still limited knowledge regarding the progression of certain cancer types. This is possibly due, in part, to our limited understanding of the tumor microenvironment that controls tumor progression, including both metastatic and angiogenic processes. Recently, cancer-associated fibroblasts (CAFs) have been described as regulators of tumor progression, and angiogenesis, via the secretion of soluble factors including vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1-alpha (HIF-1a). However, CAFs also display enhanced contractility and this biomechanical feature can promote ECM synthesis and remodeling. I hypothesized that CAF driven biomechanical forces enhance or guide angiogenesis in the peritumoral microenvironment. Utilizing 3D microtissue models, we are able to observe how CAFs impact blood vessel formation in fibrin gels. Results indicate that CAFs support increased blood vessel network formation compared to normal breast fibroblasts (NBFs), and that while soluble factors are important in this process, they are not sufficient to explain CAF supported network formation. Utilizing shRNA, inhibition of the mechanotransductive pathways of CAFs demonstrated decreased vascularization potential compared to control groups. Vascularization potential of inhibited CAFs in 3D fibrin gels was partially rescued via mechanical perturbations induced with magnetic microbeads. Taken together, the data suggests that CAFs may mechanically regulate tumor-associated angiogenesis, providing a potentially novel therapeutic target in future anti-cancer strategies.

Bio:

Dr. Sewell-Loftin received her Bachelor’s Chemical and Biological Engineering from the University of Alabama and her Doctorate in Biomedical Engineering from Vanderbilt University, where she studied in the laboratory of Dr. David Merryman. She is interested in investigating how mechanical factors drive physiological processes, using her expertise in biomaterials and microfludic-based tissue models to explore cell behaviors in both development and disease. Currently, Dr. Sewell-Loftin is a post-doctoral researcher in the lab of Dr. Gregory Longmore, in the Department of Internal Medicine at Washington University School of Medicine in St. Louis.

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