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. [Display omitted] •CRAD is reduced in colorectal tumorigenic cells responding to substrate rigidity•CRAD inhibits CRC stemness by regulating YAP transcriptional co-repressor activity•CRAD-dependent mechanical signaling dictates CRC metastasis•CRAD-F-actin-YAP axis regulates CRC progression in vivo Chang et al. demonstrate that CRAD may contribute to the antitumor function of mechanotransductive axis CRAD-F-actin-YAP in CRC progression, including stemness and metastasis. This study has implications for the prognosis and treatment of patients with CRC who display CRAD deficiency.