Substrate rigidity dictates colorectal tumorigenic cell stemness and metastasis via CRAD-dependent mechanotransduction.

Tumor physical microenvironment contributes greatly to the response of tumor cells. However, the mechanism of how extracellular substrate rigidity remodels colorectal cancer (CRC) cell fate and affects CRC progression remains elusive. Here, we show that F-actin regulator KIAA1211, also known as Capping protein inhibiting regulator of actin dynamics (CRAD), negatively correlates with CRC progression, stemness, and metastasis. Mechanistically, decreased CRAD in soft substrates induces Yes-associated protein (YAP) retention in the cytoplasm, restoring the repression effect on stemness markers NANOG and OCT4, thereby promoting CRC stemness and metastasis. Furthermore, CRAD deficiency promotes colorectal tumor cell softening and regulates epithelial-mesenchymal transition (EMT) states, contributing to its metastasis potential. Clinically, CRAD expression is correlated with malignant degrees and metastasis in CRC patients. Our work uncovers a role of CRAD in anticancer and mechanical signal transduction of the extracellular matrix in CRC.