Endothelium and subendothelial matrix mechanics modulate cancer cell transendothelial migration

Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropismAcknowledgements: The authors would like to thank all members of the RK and EM Laboratories as well as Erik Sahai (Francis Crick Institute) for critical discussions and support. E.M. is grateful for Welcome Trust-MIT Fellowship (WT103883). Y.J. and E.M. acknowledge financial support by Leverhulme Trust Research Project Grant (RPG-2018-443) and the Cancer Research UK Multidisciplinary Award (C57744/A22057). Y.J., E.M., and F.S are grateful for Biotechnology and Biological Sciences Research Council Grant (BB/V001418/1) supports. R.K. and V.S. acknowledge the support from NIH (U54CA261694). F.S. was supported by a UKRI Future Leaders Fellowship, grant number [MR/T043571/1]. F.C. was funded by MCIN/AEI/ 10.13039/501100011033 (RYC-2016-20352, RTI2018- 096778-A-I00, PID2021-128107OB-I00); AECC (LABAE19044CALV, PRYCO211372RODR); BBVA Leonardo Awards (IN[19]_BBM_BAS_0076), Cancer Research UK (C57744/A22057) and the ERC (Consolidator Grant 101045756