Abstract 3068: CD146mediates intimate crosstalk between adipocytes and triple-negative breast cancer cells and drives tumor metastasis through lipid metabolic reprogramming
Authors: Sun Hexing , Huang Kaiyuan , Sun Bingmei , Lin Jiajia , Yang Ruiqian , Li Jiawei , Wang Shimeng , Zeng De , Lin Haoyu , Liang Yuanke 
Published: March 2024

Background & Aim: In the tumor microenvironment, the adipocytes enhance the invasiveness of breast cancer (BC) by remodeling the lipid metabolism, especially in triple-negative breast cancer (TNBC). The cell adhesion molecule CD146 was highly expressed in TNBC and predicted poor distant metastasis free survival (DMFS) in patients. Meanwhile, CD146 was known to alter the obesity process by regulating the metabolic level of the body. In this study, we aimed to explore the molecular mechanism of CD146 in tumor metastasis mediating by lipid metabolic reprogramming between adipocytes and TNBC cells.

Methods: CD146 knockout (KO) or overexpression cell models were constructed by CRISPR/Cas9 or lentivirus. Cells labeled with luciferase were injected in tail vein of Balb/c-nude mice and monitored lung metastasis by IVIS Kinetic system in vivo. Transwell and wound healing assays were analyzed cell aggressiveness in vitro. We synthesized anti-CD146 nanobodies, which significantly degraded CD146 protein and inhibitd its function. RNA-seq and Lipidomics in CD146 knockout models were performed to analyze the role of CD146 in TNBC cell metabolism. Immunofluorescence was used to detect the intracellular content of Lipid Droplet (LD) and protein localization. Finally, we used oleic acid (OA) and adipocyte-conditioned medium (CM) to mimic the tumor microenvironment.

Results: CD146 was highly expressed in TNBC and predicted poor DMFS survival. Inhibition of CD146 suppressed tumor aggressiveness and lung metastasis in vitro and in vivo. According to the bioinformatics and RNA-Seq analysis, we showed that CD146 was intimately involved in the lipid metabolic pathway, particularly fatty acid metabolism, and revealed that inhibiting CD146 in TNBC elevated the intracellular triglyceride level through lipidomic assay. Meanwhile, knockout of CD146 promoted LD accumulation and decreased fatty acid oxidation (FAO) and mitochondrial ATP levels. In molecular mechanism, we found that adipocytes secrete high level of IL6 and fatty acid, which activated JAK/STAT3 signaling and FAO mediating by CD146 in TNBC cells. Blocking CD146 using its nanobody inhibited IL6/JAK/STAT3 activities and ACADM, leading to impairment of FAO and lung metastasis suppression in vitro and in vivo.

Conclusions: In this study, we demonstrate the crucial role of CD146 in the crosstalk between tumor cells and adipocytes in the tumor microenvironment. CD146 promotes the utilization of fatty acids through fatty acid oxidation and activates the downstream inflammatory pathway response with adipocyte-secreted IL-6, thereby driving BC aggressiveness. Our study has important implications for the development of TNBC therapeutics to block CD146-driven FAO process, inflammatory response and tumor metastasis.

Citation Format: Hexing Sun, Kaiyuan Huang, Bingmei Sun, Jiajia Lin, Ruiqian Yang, Jiawei Li, Shimeng Wang, De Zeng, Haoyu Lin, Yuanke Liang. CD146mediates intimate crosstalk between adipocytes and triple-negative breast cancer cells and drives tumor metastasis through lipid metabolic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3068.