TFEB is a master regulator of tumor-associated macrophages in breast cancer
TFEB is a master regulator of tumor-associated macrophages in breast cancer
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TFEB是乳腺癌中肿瘤相关巨噬细胞的主要调节因子
DOI：
10.1136/jitc-2020-000543
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Fan, Daping
中科院分区：
文献类型：
--
作者：
Li, Yong;Hodge, Johnie;Fan, Daping
背景肿瘤相关巨噬细胞（TAMs）在包括乳腺癌在内的许多恶性实体瘤的发生发展中起关键作用。他们在肿瘤微环境（TME）中接受教育，以促进肿瘤生长，转移和治疗抗性。然而，TAM的表型是难以捉摸的，如何调节它们以达到治疗目的仍然不清楚;因此，TAM靶向治疗尚未取得临床成功。本研究的目的是研究转录因子EB（TFEB）在调节TAM基因表达和功能中的作用，并确定TFEB激活是否可以阻止乳腺肿瘤的发展。方法采用基因芯片分析乳腺癌巨噬细胞（M phi s）的基因表达谱，并检测TFEB过表达的影响。进行细胞培养研究以确定TFEB影响M phi基因表达和功能的机制。进行小鼠研究以研究M phi TFEB缺乏或活化对乳腺肿瘤生长的影响。分析人类癌症基因组数据以揭示TFEB及其调控基因的预后价值。结果TAM模拟M phi s具有独特的基因表达谱，TFEB表达显著降低。TFEB过表达通过多种信号通路有利地调节TAM基因表达。具体地，TFEB上调细胞因子信号传导抑制因子3（SOCS 3）和过氧化物酶体增殖物激活受体γ（PPR）。（PPAR γ）表达和自噬/溶酶体活性，抑制NLRP 3（NLR家族Pyrin结构域包含3）炎性体和低氧诱导因子（HIF）-1 α介导的低氧应答，从而抑制TAM中的一系列效应分子，包括腺苷酸酶1，白细胞介素（IL）-10，IL-1 β、IL-6和前列腺素E2。当使用天然二糖海藻糖激活TFEB时，M phi特异性TFEB缺陷通过调节TAM促进乳腺肿瘤发展。对人类患者基因组数据库的分析揭示，TFEB、SOCS 3和PPAR γ的表达水平是乳腺癌的阳性预后标志物，而HIF-1 α是乳腺癌的阴性预后标志物。结论我们的研究确定TFEB是乳腺癌TAM的主要调节因子。TFEB通过多种自噬/溶酶体依赖性和非依赖性途径控制TAM基因表达和功能。因此，TFEB的药理学活化将是一种有前景的治疗方法，通过有利地调节TAM功能和TME来改善现有治疗（包括乳腺癌的免疫治疗）的功效。
Background Tumor-associated macrophages (TAMs) play key roles in the development of many malignant solid tumors including breast cancer. They are educated in the tumor microenvironment (TME) to promote tumor growth, metastasis, and therapy resistance. However, the phenotype of TAMs is elusive and how to regulate them for therapeutic purpose remains unclear; therefore, TAM-targeting therapies have not yet achieved clinical success. The purposes of this study were to examine the role of transcription factor EB (TFEB) in regulating TAM gene expression and function and to determine if TFEB activation can halt breast tumor development. Methods Microarrays were used to analyze the gene expression profile of macrophages (M phi s) in the context of breast cancer and to examine the impact of TFEB overexpression. Cell culture studies were performed to define the mechanisms by which TFEB affects M phi gene expression and function. Mouse studies were carried out to investigate the impact of M phi TFEB deficiency or activation on breast tumor growth. Human cancer genome data were analyzed to reveal the prognostic value of TFEB and its regulated genes. Results TAM-mimic M phi s display a unique gene expression profile, including significant reduction in TFEB expression. TFEB overexpression favorably modulates TAM gene expression through multiple signaling pathways. Specifically, TFEB upregulates suppressor of cytokine signaling 3 (SOCS3) and peroxisome proliferator-activated receptor gamma (PPAR gamma) expression and autophagy/lysosome activities, inhibits NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome and hypoxia-inducible factor (HIF)-1 alpha mediated hypoxia response, and thereby suppresses an array of effector molecules in TAMs including arginase 1, interleukin (IL)-10, IL-1 beta, IL-6 and prostaglandin E2. M phi-specific TFEB deficiency promotes, while activation of TFEB using the natural disaccharide trehalose halts, breast tumor development by modulating TAMs. Analysis of human patient genome database reveals that expression levels of TFEB, SOCS3 and PPAR gamma are positive prognostic markers, while HIF-1 alpha is a negative prognostic marker of breast cancer. Conclusions Our study identifies TFEB as a master regulator of TAMs in breast cancer. TFEB controls TAM gene expression and function through multiple autophagy/lysosome-dependent and independent pathways. Therefore, pharmacological activation of TFEB would be a promising therapeutic approach to improve the efficacy of existing treatment including immune therapies for breast cancer by favorably modulating TAM function and the TME.