三阴性乳腺癌细胞通过CPT1A的外泌活化内皮细胞脂肪酸β氧化促进肿瘤血管生成的机制研究

The tumor microenvironment (TME) is modeled by cancer cells for their own benefit to survival or growth. Lipid metabolism reprogramming plays a key role in the regulation of the TME by cancer cells. Recently we found that carnitine palmitoyl transferase 1A (CPT1A), the key rate-limiting enzyme in the process of fatty acid oxidation (FAO), was expressed in the exosomes of triple-negative breast cancer (TNBC) cells. The plasma levels of CPT1A were elevated in breast cancer patients and were associated with tumor metastasis. Thus, this project aims to clarify the importance of CPT1A in TNBC. We will further explore the correlation between tumor progression and the plasma levels of CPT1A in TNBC patients. Based on the significance of the communication within the TME and cancer cells, we will investigate the regulation of metabolic reprogramming and angiogenesis in endothelial cells (ECs) by exosomal CPT1A derived from TNBC cells. Then we will study on the epigenetic mechanism involved in the regulation of angiogenic genes in ECs by CPT1A. This project will help us deeply understand the role of CPT1A in tumor environment, and provide new evidences for developing novel targeting therapeutic strategy and prognostic marker of TNBC.

肿瘤细胞对微环境的改造是肿瘤进展的重要机制。脂代谢重编程在肿瘤细胞对微环境的调控中发挥关键作用。新近我们发现介导脂肪酸β氧化的关键分子CPT1A在三阴性乳腺癌细胞的外泌体中表达，乳腺癌患者的血浆CPT1A水平增高并与乳腺癌转移相关。本项目将以CPT1A为重点，以三阴性乳腺癌为研究模型，从临床角度进一步研究血浆CPT1A水平与乳腺癌进展的相关性；以肿瘤细胞与微环境的相互作用为切入点，分析三阴性乳腺癌细胞的外泌体CPT1A对内皮细胞脂代谢重编程及血管生成能力的调控作用；从表观遗传学角度研究CPT1A的外泌对内皮细胞血管生成相关基因的调控机制。本项目为研究CPT1A在肿瘤微环境中的作用机制提供新的实验依据，为三阴性乳腺癌的治疗及预后评估提供新的分子靶点。

肿瘤细胞对微环境的重塑是肿瘤进展的重要机制。脂代谢重编程在肿瘤与微环境的相互作用中发挥关键作用。本项目以肿瘤细胞与微环境的相互作用为切入点，以脂肪酸氧化关键调控分子CPT1A为重点，先从临床角度展开研究，发现血清CPT1A可作为乳腺癌血清学诊断标志物，并与乳腺癌进展、分子分型和患者预后密切相关。在机制方面，本项目发现CPT1A在三阴性乳腺癌细胞和外泌体中高表达，三阴性乳腺癌细胞的外泌体CPT1A激活内皮细胞的脂肪酸β氧化，促进乙酰辅酶A的生成，并通过表观遗传学调控机制，增加组蛋白乙酰化水平，上调VEGFR3等血管生成相关基因的表达，从而促进三阴性乳腺癌细胞的侵袭转移。本项目为研究CPT1A在肿瘤微环境中的作用机制提供新的实验依据，为三阴性乳腺癌的治疗及预后评估提供新的分子靶点。