P-cadherin mechanoactivates tumor- mesothelium metabolic coupling to promote ovarian cancer metastasis

Abstract

Peritoneal metastasis exacerbates the prognosis of ovarian cancer patients. Adhesion of cancer cells to mesothelium is a rate-limiting prerequisite for this process. How metastatic cells sense and respond to the dynamic biomechanical microenvironment at the mesothelial niche to initiate metastatic lesions remains unclear. Here, the study demonstrates that highly metastatic (HM), but not non-metastatic (NM) ovarian cancer cells, selectively activate the peritoneal mesothelium. Atomic force microscopy reveals that HM cells exert increased adhesive force on mesothelial cells via P-cadherin, a cell-cell adhesion molecule abundant in late-stage tumors. Transcriptomic and molecular analyses show that mechanical induction of P-cadherin enhances lipogenic gene expression and lipid content in HM cells by SREBP1. P-cadherin activation does not affect lipogenic activity but induces glycolysis in the interacting mesothelium. Targeted lipidomic analysis reveals that lactate produced by the glycolytic mesothelium facilitates metastatic outgrowth as a direct substrate for de novo lipogenesis. Inhibiting lactate shuttling via nanodelivery of siRNA targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. The association of high fatty acid synthase in patient metastatic samples and increased P-cadherin expression supports enhanced de novo lipogenesis in the metastatic niche. The study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain peritoneal metastasis.