Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness.

An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumors. By shotgun proteomics of decellularized human BCs, we found a significant enrichment in proteins involved in tumor-ECM interaction in E3G3 tumors. These tumors were characterized by high dense collagen deposition, a fibrillary cytoskeleton network and the highest stiffness. CLEC3A, a secreted C-type lectin domain family 3 member, was found unique of E3G3 tumors and was validated to be more expressed in these tumors by immunohistochemistry in 2 human BC cohorts, associating significantly with worse prognosis. Ectopic CLEC3A overexpression in MDA-MB-231, MDA-MB-361, and MDA-MB-468 BC cells increased intracellular mediators of tumor adhesion to the ECM, actin-stress fibers and YAP activation, and tumor migration. Accordingly, levels of the YAP/TAZ gene signature were higher in CLEC3A-positive ECM3-enriched tumors and correlated with tumor stiffness. These results implicate CLEC3A in mediating the ability of E3G3 BCs to sense cues in the surrounding ECM, accelerating tumor progression.