ICAP-1 alternative splicing regulates Talin tension polarization in NSCLC durotaxis.

The directional migration of cancer cells in response to tumor microenvironment stiffening is mediated through integrin-dependent mechanotransduction pathways, particularly involving integrin cytoplasmic domain-associated protein 1 (ICAP-1). In this study, we aimed to explore the role of Talin tension during directional migration of non-small cell lung cancer (NSCLC) cells, with a specific focus on the isoform-specific regulation by ICAP-1α and ICAP-1β. Our findings demonstrate that matrix stiffening triggers a significant shift in ICAP-1 isoform expression. ICAP-1α, but not ICAP-1β, reduces the aggressiveness and directionality of NSCLC cells on a cell-directed matrix (CDM) with a stiffness gradient. ICAP-1α exhibited an extensive subcellular distribution, which inhibits integrin activity and talin tension. Our results establish ICAP-1 as a critical mechanotransducer that relays signals from β1-integrin to Talin, and suggest that ICAP-1 alternative splicing could be harnessed as a potential therapeutic strategy for NSCLC.