赖氨酸代谢介导TrkB+亚群参与三阴性乳腺癌复发转移的机制研究

Cancer stem cells (CSCs) are a heterogeneous subpopulation of cancer cells，in which the TrkB+CSCs are responsible for post-therapeutic relapse of triple-negative breast cancer (TNBC). However, the underlying mechanisms during this process are still elusive. In our preliminary studies, we developed a TNBC mouse model of post-therapeutic recurrence. By performing a genome-wide transcriptome analysis, we observed that lysine catabolism was initiated while fatty acid synthesis was suppressed in the TrkB+CSCs from recurrent lesions. Here, we aim to uncover the critical role of lysine catabolism in TrkB+CSCs-mediated TNBC relapse both in vitro and in vivo. Utilizing RNAi, ChIP-PCR and promoter reporter system, we attempt to clarify the potential epigenetic mechanisms involved in metabolic reprogramming of the TrkB+CSCs. Moreover, with a lentiviral-based knockdown approach, we try to determine whether disrupting lysine catabolism in vivo represents a novel therapeutic approach to prevent post-therapeutic relapse and metastasis of TNBC. Thus, further support of this program would provide a new insight into the process of TNBC relapse and a promising perspective for anti-TNBC therapy.

肿瘤干细胞（CSCs）是具有功能异质性的细胞亚群，其中TrkB+CSCs在三阴性乳腺癌（TNBC）复发转移过程中发挥了重要作用。目前，TrkB+CSCs在干性维持、调控化疗抗性和侵袭转移中的作用和规律尚未阐明。我们在前期研究中利用三阴性乳腺癌复发转移模型和高通量筛选等方法，初步证实TNBC复发灶内的TrkB+CSCs发生了代谢重编程，即开启赖氨酸代谢合并抑制脂肪合成代谢。本项目拟利用人TNBC细胞系、人TNBC标本和小鼠体内模型，从体内外两方面进一步证实赖氨酸代谢介导TrkB+CSCs参与TNBC复发转移的作用；采用RNAi、ChIP-PCR、启动子报告基因等技术，阐明TrkB+CSCs发生代谢重编程的表观调控机制；并通过动物实验观察靶向干扰赖氨酸代谢对抑制TNBC复发转移的作用，从而为有效改善TNBC临床预后提供新策略和新方法。

肿瘤干细胞（cancer stem cells, CSCs）是具有功能异质性的细胞亚群，其中TrkB+CSCs在三阴性乳腺癌（triple-negative breast carcinoma, TNBC）复发转移过程中发挥了重要作用。目前，TrkB+CSCs在干性维持、调控化疗抗性和侵袭转移中的作用和规律尚未阐明。在本项研究中，我们发现TNBC复发灶内的TrkB+CSCs在BDNF (brain-derived neurotrophic factor)作用下发生了代谢重编程，即开启赖氨酸代谢合并抑制脂肪合成代谢。赖氨酸代谢产生的乙酰辅酶A通过乙酰化Foxd3，保护其不被泛素化降解，从而促进了TrkB+CSCs的自我更新潜能。另一方面，赖氨酸代谢通路主要副产物谷氨酸通过合成谷胱甘肽，帮助TrkB+CSCs逃避化疗药物引起的氧化应激损伤。BDNF诱导TrkB+CSCs所表达的KLF4通过介导表观遗传修饰，开启了TrkB+CSCs的代谢重编程。因此，靶向赖氨酸代谢能够成为潜在的有效预防三阴性乳腺癌术后复发转移的治疗靶点。