Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state.

Abstract

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 and seeding liver metastases are devoid of Lgr5 expression. Using CRC organoid models, we demonstrate that mechanical interactions with collagen I, a main constituent of the interstitial matrix, instruct the reprogramming of CRC cells. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a cellular state with transcriptional similarities to fetal intestinal cells. CRC cells infiltrating the interstitial stroma show upregulation of this fetal-like transcriptional program, which correlates with the ability of Lgr5-negative cells to initiate metastasis formation. Our findings indicate that mechanical interactions with collagen I regulate cell fate transitions associated with the metastatic cascade of CRC.