TY - UNPB
T1 - Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation
AU - Net, Mirjam van der
AU - Vliem, Marjolein J
AU - Kemp, Lars
AU - Perez-Gonzalez, Carlos
AU - Strating, Esther A
AU - Krotenberg-Garcia, Ana
AU - Houtekamer, Ronja
AU - Anker, Karen B van den
AU - Monster, Jooske
AU - Snippert, Hugo
AU - Khalil, Antoine A.
AU - Rheenen, Jacco van
AU - Suijkerbuijk, Saskia J E
AU - Kranenburg, Onno
AU - vignjevic, Danijela Matic
AU - Gloerich, Martijn
PY - 2023/9/17
Y1 - 2023/9/17
N2 - Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms.
AB - Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms.
U2 - 10.1101/2023.09.17.557771
DO - 10.1101/2023.09.17.557771
M3 - Preprint
SP - 1
EP - 24
BT - Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation
PB - bioRxiv
ER -