Matrix rigidity is a critical contributor to tumor progression; however, whether and how matrix stiffness modulates the collective invasion of tumor cells remain unknown. Here we demonstrate that increased matrix stiffness activates YAP to promote the secretion of periostin (POSTN) in cancer-associated fibroblasts, which in turn augments the matrix rigidity of mammary glands and breast tumor tissues by facilitating collagen crosslinking. Moreover, decreased tissue stiffening resulted from the POSTN deficiency impairs peritoneal metastatic potential of orthotopic breast tumors. Increased matrix stiffness also promotes three-dimensional (3D) collective breast tumor cell invasion via multicellular cytoskeleton remodeling. POSTN triggers the integrin/FAK/ERK/Cdc42/Rac1 mechanotransduction pathway during 3D collective invasion of breast tumor. Clinically, high POSTN expression correlates with high collagen levels in breast tumors and cooperatively determines the metastatic recurrence potential in breast cancer patients. Collectively, these findings indicate that matrix rigidity promotes 3D collective invasion of breast tumor cells via the YAP-POSTN-integrin mechanotransduction signaling.

基质刚性是肿瘤进展的关键因素；然而，基质硬度是否以及如何调节肿瘤细胞的集体侵袭仍然未知。在这里，我们证明增加的基质硬度会激活 YAP，促进癌症相关成纤维细胞分泌骨膜素 (POSTN)，从而通过促进胶原交联来增强乳腺和乳腺肿瘤组织的基质硬度。此外，POSTN 缺陷导致的组织硬化减少会损害原位乳腺肿瘤的腹膜转移潜力。基质硬度的增加还通过多细胞细胞骨架重塑促进三维（3D）集体乳腺肿瘤细胞侵袭。POSTN 在乳腺肿瘤 3D 集体侵袭过程中触发整合素/FAK/ERK/Cdc42/Rac1 机械转导通路。临床上，高 POSTN 表达与乳腺肿瘤中的高胶原水平相关，并共同决定乳腺癌患者的转移复发潜力。总的来说，这些发现表明基质刚性通过 YAP-POSTN-整合素机械转导信号促进乳腺肿瘤细胞的 3D 集体侵袭。