A new paper written by an interdisciplinary team reveals the alarming impact mechanical strain can have on breast cancer cells by creating conditions that could lead to dangerous acceleration of the disease
UAB faculty Joel Berry, Ph.D., associate professor in the Department of Biomedical Engineering; Jessy Deshane, Ph.D., associate professor in the UAB School of Medicine; Roy Koomullil, Ph.D., associate professor in the Department of Mechanical Engineering, and Selvarangan Ponnazhagan, Ph.D., professor in the Department of Pathology, have joined forces to study how the biomechanics of breast tumors influence immune suppression. The group recently published a paper entitled, “Mechanical Strain Induces Phenotypic Changes in Breast Cancer Cells and Promotes Immunosuppression in the Tumor Microenvironment” in the journal Laboratory Investigation. (Wang Y, Goliwas K, Severino P, Hough K, Van Vessem D, Wang H, Tousif S, Koomullil R, Frost A, Ponnazhagan S, Berry J, Deshane J. 2020 Jun 22. doi: 10.1038/s41374-020-0452-1. Online ahead of print). This collaboration also led to a June 2020 R01 submission of a Multi-PI proposal to the National Cancer Institute’s special announcement Cancer Tissue Engineering Collaborative: Enabling Biomimetic Tissue-Engineered Technologies for Cancer Research.
As breast tumors grow, biomechanical forces in the tumor microenvironment (TME) cause elevated compression at the tumor interior, tension at the periphery, and altered interstitial fluid flow—promoting aggressive growth, invasion, and metastasis. Biomechanical forces may also modulate the immune response through cancer cell–immune cell crosstalk. Among intercellular mediators of signaling in the TME, tumor cell–secreted exosomes are now recognized as key regulators of tumor progression.
The group’s novel tissue-engineered three-dimensional breast cancer mimetic system recapitulates the in vivo growth of breast cancer cells in the presence of tumor-associated fibroblasts, endothelial cells, and immune cells, within a physiologically relevant extracellular matrix. They found that biomechanical forces significantly altered the proteome of breast cancer cells and enhanced exosome production. These exosomes directly promoted aggressive tumor cell growth, induced immune suppression, and altered immune cell polarization in the TME. Further, their recently engineered oscillatory compression device for real-time application of biomechanical force on orthotopic mammary tumors in vivo, allowed them to observe exosome-mediated immunosuppression and aggressive tumor growth in mice.
Preliminary analyses of exosome migration, immune cell uptake and polarization superimposed onto a novel computational algorithm indicated the significance of exosome concentration gradient and time in predicting the kinetics of protumorigenic events, linking biomechanical force, exosome release by tumor cells, exosome uptake, and polarization of immune cells in the TME.