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

Cancer adhesion to the mesothelium is critical for peritoneal metastasis, but how metastatic cells adapt to the biomechanical microenvironment remains unclear. Our study demonstrates that highly metastatic (HM), but not non-metastatic, ovarian cancer cells selectively activate the peritoneal mesothelium. HM cells exert a stronger adhesive force on mesothelial cells via P-cadherin, an adhesion molecule abundant in late-stage tumors. Mechanical activation of P-cadherin enhances lipogenic gene expression and lipid content in HM cells through SREBP1. P-cadherin also induces glycolysis in the interacting mesothelium without affecting lipogenic activity, with the resulting lactate serving as a substrate for lipogenesis in HM cells. Nanodelivery of small interfering RNA (siRNA) targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. Moreover, increased fatty acid synthase levels in metastatic patient samples correlate with high P-cadherin expression, supporting enhanced de novo lipogenesis in the metastatic niche. This study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain metastasis. Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Jing Ma, Sally Kit Yan To, Katie Sze Wai Fung, Kun Wang, Jiangwen Zhang, Alfonso Hing Wan Ngan, Susan Yung, Tak Mao Chan, Carmen Chak Lui Wong, Philip Pun Ching Ip, Ling Peng, Hong-Yan Guo, Chi Bun Chan, Alice Sze Tsai Wong. P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis. Cell reports. 2025 Jan 28;44(1):115096

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PMID: 39700008

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