Kavli Affiliate: Denis Wirtz
| Authors: Alexandra Sneider, Ying Liu, Bartholomew Starich, Wenxuan Du, Carolyn Marar, Najwa Faqih, Gabrielle E Ciotti, Joo Ho Kim, Sejal Krishnan, Salma Ibrahim, Muna Igboko, Alexus Locke, Daniel M Lewis, Hanna Hong, Michelle Karl, Raghav Vij, Gabriella C Russo, Praful R Nair, Estibaliz Gómez-de-Mariscal, Mehran Habibi, Arrate Munoz-Barrutia, Luo Gu, T. S. Karin Eisinger-Mathason and Denis Wirtz
| Summary:
Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiological matrix stiffness affects the quantity and protein cargo of small EVs produced by cancer cells, which in turn drive their metastasis. Primary patient breast tissue produces significantly more EVs from stiff tumor tissue than soft tumor adjacent tissue. EVs released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature increased adhesion molecule presentation (ITGα2β1, ITGα6β4, ITGα6β1, CD44) compared to EVs from softer normal tissue (0.5 kPa; soft EVs), which facilitates their binding to extracellular matrix (ECM) protein collagen IV, and a 3-fold increase in homing ability to distant organs in mice. In a zebrafish xenograft model, stiff EVs aid cancer cell dissemination through enhanced chemotaxis. Moreover, normal, resident lung fibroblasts treated with stiff and soft EVs change their gene expression profiles to adopt a cancer associated fibroblast (CAF) phenotype. These findings show that EV quantity, cargo, and function depend heavily on the mechanical properties of the extracellular microenvironment.