P-cadherin activates metabolic coupling in the tumor-mesothelial niche: From glycolysis through lactate to lipogenesis

Peritoneal metastasis affects >70% ovarian cancer patients, and its effective management is an unmet medical goal. Successful adhesion to the peritoneal mesothelium is a key rate-limiting step for metastasis formation, but it is unclear the selective advantage of why ovarian cancer cells colonize specifically to the unique mesothelial environment. Metabolic reprogramming is a hallmark of cancers. Still their role in peritoneal metastasis remains to be fully understood. To overcome the limitations of a lack of tightly controlled experimental model to pinpoint key molecules causing metastasis, we have established an isogenic model of spontaneous human ovarian cancer metastasis. Metabolism is characterized using RNA-seq, RT-PCR, real-time cell metabolic assay, targeted lipidomic analysis and neutral lipid staining. Using coculture, we showed that HM but not NM specifically activated peritoneal mesothelium in a P-cadherin-dependent manner compared to other cadherins, suggesting that there is a unique role for P-cadherin. RNA-seq revealed distinct regulation of lipogenic pathway in non-specific or P-cadherin siRNA treated HM. For these, we have confirmed that P-cadherin could promote the expression of lipogenic genes ACLY, FASN and ACAT2 in HM. Concomitantly, P-cadherin activated glycolysis (HK2, Gpi and PGK1) in the mesothelial cells. Targeted lipidomic analysis further showed that lactate acid that was enriched in the mesothelium was shuttled from the mesothelium to the HM to fuel de novo lipid synthesis in HM, revealing a feed-forward positive loop. Suppressing lactate uptake by using a monocarboxylate transporter 1 inhibitor could abolish the metabolic crosstalk and subsequent metastatic outgrowth. Together, these findings reveal the metabolic differences between metastatic versus non-metastatic tumor cells in understanding ovarian cancer metastasis to the mesothelium, and suggest targeting P-cadherin could be a promising therapeutic approach (RGC17105919). Citation Format: Kun Wang, Jing Ma, Carmen C. L. Wong, Chi Bun Chan, Alice S. T. Wong. P-cadherin activates metabolic coupling in the tumor-mesothelial niche: From glycolysis through lactate to lipogenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P130.