PT - JOURNAL ARTICLE AU - Vasileios Papalazarou AU - James Drew AU - Amelie Juin AU - Heather J. Spence AU - Colin Nixon AU - Manuel Salmeron-Sanchez AU - Laura M. Machesky TI - Collagen-VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche AID - 10.1101/2022.03.03.482797 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.03.03.482797 4099 - http://biorxiv.org/content/early/2022/03/03/2022.03.03.482797.short 4100 - http://biorxiv.org/content/early/2022/03/03/2022.03.03.482797.full AB - Pancreatic cancer is a deadly disease with high rates of metastasis, though how tumor cells establish metastatic lesions is not fully understood. A key feature of primary pancreatic tumors is extensive fibrosis due to deposition of extracellular matrix. While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment as well as adaptation to a softer microenvironment upon reaching distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing of soft substrates. Through use of engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that Collagen-VI is specifically upregulated on soft substrates, due to a lack of integrin engagement and low YAP1 activity. Collagen-VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 expression, were characterised by stromal cell-derived collagen-VI deposition, suggesting that collagen-VI, either cancer or stroma derived, is an essential component of the metastatic niche.Summary Statement Collagen-VI is expressed by pancreatic tumors and metastases in a mechanosensitive way to promote niche colonisation.Competing Interest StatementThe authors have declared no competing interest.