巨噬细胞促前列腺癌细胞代谢重编程为神经内分泌型的机制及其应用研究

新一代AR拮抗剂进入临床后，神经内分泌型前列腺癌（NEPC）的发病率升高，占耐药性前列腺癌的四分之一，尚无有效治疗方案。NEPC是前列腺癌发生上皮间质转化，进而转分化为神经内分泌肿瘤细胞，以组蛋白甲基转移酶EZH2高表达介导H3K27m3升高为主要分子特征。我们前期结果发现，NEPC中有大量巨噬细胞聚集，在其形成中发挥重要作用。结果进一步提示，巨噬细胞可能通过竞争性摄取微环境中的谷氨酰胺，诱导前列腺癌细胞代谢重编程，降低胞内alpha-酮戊二酸浓度，抑制了alpha-酮戊二酸依赖的组蛋白去甲基酶的活性，与AR拮抗剂诱导的EZH2协同作用，维持胞内H3K27m3的高水平。本课题将在患者来源的类器官与巨噬细胞共培养的NEPC体外模型中验证以上假说，更提出通过免疫疗法改变巨噬细胞极性，降低谷氨酰胺的摄取，与EZH2抑制剂等来协同治疗NEPC的新方案。本课题将推动NEPC机制和治疗的探索。

Since the new generation of AR antagonists aare used in clinic, more and more patients with neuroendocrine prostate cancer (NEPC) appeared and the case number almost reached the one fourth of drug-resistant prostate cancer, and so far there was no effective treatments for NEPC. NEPC are formed by the epithelial-mesenchymal transition of prostate cancer and retransformed to neuroendocrine cancer cells. The molecular hallmark of NEPC is high level of H3K27m3 induced by histone methyltransferase EZH2. Our preliminary data found that there were a lot of macrophages accumulated in NEPC and play an important role during NEPC formation. Further results suggested that macrophages might competitively use glutamine in microenvironment, induce metabolic reprogram to decrease the level of -KG in tumor cells and inhibit the activity of -KG-dependent histone demethylases to maintain the high level of H3K27m3 by synergy with AR antagonist-induced EZH2. This project will establish the in vitro NEPC model by co-culture macrophages with prostate-cancer-patient-derived organoids and confirm our hypothesis in this model. What’s more, we pointed out the new idea of combination of immunotherapy to modify the activity of macrophages and the EZH2 inhibitors for treatment of NEPC. The study of this project will play an important role to improve the understanding of the mechanism of NEPC formation and treatments.