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.
Authors
- Ling Peng (ORCID: https://orcid.org/0000-0003-3990-5248)
- Alice S.T. Wong (ORCID: https://orcid.org/0000-0002-0676-6475)
- Philip P.C. Ip (ORCID: https://orcid.org/0000-0002-0493-9838)
- Katie Sze Wai Fung
- Hongyan Guo (ORCID: https://orcid.org/0000-0001-6917-5341)
- Jiangwen Zhang (ORCID: https://orcid.org/0000-0002-2911-8446)
- Kun Wang (ORCID: https://orcid.org/0000-0001-5910-1568)
- Tak Mao Chan (ORCID: https://orcid.org/0000-0002-3495-4051)
- Carmen Chak‐Lui Wong (ORCID: https://orcid.org/0000-0001-5866-4705)
- Chi Bun Chan (ORCID: https://orcid.org/0000-0002-2787-9575)
- Jing Ma (ORCID: https://orcid.org/0000-0001-6347-8552)
- Susan Yung
- A.H.W. Ngan (ORCID: https://orcid.org/0000-0002-9299-1504)
- Sally Kit Yan To
Institutions
- Centre National de la Recherche Scientifique (FR)
- Cato Institute (US)
- Shenzhen University (CN)
- Peking University (CN)
- Aix-Marseille Université (FR)
- Queen Mary Hospital (CN)
- State Key Laboratory of Synthetic Chemistry (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Peking University Third Hospital (CN)
- Centre Interdisciplinaire de Nanoscience de Marseille (FR)
- University of Hong Kong (HK)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.celrep.2024.115096
- Citations
- 9
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- Research Grants Council, University Grants Committee
- Innovation and Technology Commission - Hong Kong
- Shenzhen Science and Technology Innovation Program