Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer

雌激素受体限制 K-ras 突变肺癌中促肿瘤的炎症

• 批准号: 10583464
• 负责人: Michael Joseph Clowers
• 金额: $ 3.52万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583464
• 关键词: Ablation; Bone Marrow Transplantation; Cancer Etiology; Cells; Cessation of life; Clinical Trials; DNA Sequence Alteration; Development; Epithelium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Female; Genes; Genetic; Genotype; Goals; Gonadal Steroid Hormones; Immune; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-6; Knock-out; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modality; Modeling; Mus; Mutant Strains Mice; Mutate; Mutation; Myelogenous; Myeloid Cells; Nuclear Hormone Receptors; Outcome; Pathway interactions; Patients; Phenotype; Play; Production; Proliferating; Protein Isoforms; Rattus; Receptor Gene; Receptor Signaling; Risk; Role; STAT3 gene; Signal Transduction; Smoker; Structure of parenchyma of lung; System; Testing; Tumor Burden; Tumor Immunity; Tumor Promotion; Tumor-infiltrating immune cells; United States; Viral Oncogene; cancer clinical trial; cancer type; carcinogenesis; cell type; cigarette smoke; comparison control; driver mutation; druggable target; female sex hormone; individualized medicine; inhibitor; interest; male; men; mutant; neoplastic cell; novel therapeutics; personalized medicine; promoter; receptor binding; recruit; resistance mechanism; resistance mutation; sarcoma; sex; sex disparity; single-cell RNA sequencing; targeted treatment; transcription factor; tumor; tumor microenvironment; tumorigenesis

Abstract More patients die from lung cancer than from any other cancer type each year in the United States. Moreover, lung cancers with K-ras driver mutations are resistant to targeted therapies. Therefore, there is an unmet need to find druggable targets downstream of K-ras. Tumor-promoting inflammation occurs frequently as a result of K-ras mutations that activate the NF-κB pathway, the production of interleukin 6, and activation of its downstream transcription factor STAT3. However, when we knock out STAT3 in tumor cells in mice, females have fewer tumors, but males have more. This sex disparity is driven by overactivation of NF-κB in males, but in females, estrogen signaling reduces NF-κB and tumor-promoting inflammation. This protective phenotype requires estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-κB. There are two genes for ERs: ERα and ERβ. ERβ is the major ER isoform expressed in lung tissue, and ERα is mainly in immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERα and ERβ signaling is protective in K-ras mutant lung cancer by inhibiting NF-κB-driven pro-tumor inflammation. I have two specific aims to test this hypothesis, one aim for each of the cellular compartments of interest: tumor cells and myeloid cells. Aim 1: I will knock out ERβ in tumors to determine if it is required for cancer protection in females. Aim 2: since ERα predominates in tumor-infiltrating myeloid immune cells, I will knock out ERα in myeloid cells to determine if it is also required for cancer protection. Successful completion of these aims will further explain the mechanism of ER-dependent lung cancer protection, with potential for estrogen and ERα/ERβ to play a novel therapeutic role. Since clinical trials for STAT3 inhibitors have begun, it is important to understand the sex- specific outcomes of targeting STAT3. Our results will guide clinicians to better personalize therapy by taking sex hormones into account when treating patients. They will also shed light on the mechanism of resistance to currently available immunotherapies and provide alternative modalities.

摘要 在美国，每年死于肺癌的患者比死于任何其他癌症类型的患者都多。此外， 携带K-ras基因突变的肺癌对靶向治疗具有抵抗力。因此，有一种未得到满足的需求。 寻找K-ras下游的可用药靶点。促进肿瘤的炎症经常发生，原因是 激活核因子-κB途径、产生白介素6及其下游激活的K-ras突变 转录因子STAT3。然而，当我们在小鼠的肿瘤细胞中敲除STAT3时，雌性小鼠的 肿瘤，但男性有更多。这种性别差异是由男性体内核因子-κB的过度激活造成的，但在女性中， 雌激素信号可减少核因子-κB和促癌炎症。这种保护性表型需要 雌激素受体(ER)是一种与雌激素结合并与核因子-κB相互作用的核激素受体。 ER基因：ERα和ERβ。ER-β是肺组织表达的主要ER亚型，ER-α主要存在于 免疫细胞。因此，我推测，在肺上皮细胞中没有STAT3的情况下，ERα和ERβ 在K-ras突变肺癌中，信号通过抑制NF-κB驱动的促肿瘤炎症而起到保护作用。我有两个 为了验证这一假说，每个感兴趣的细胞隔间都有一个目标：肿瘤细胞和 髓系细胞。目的1：我将敲除肿瘤中的ERβ，以确定它是否是女性癌症预防所必需的。 目的2：由于ERα主要存在于肿瘤浸润性髓系免疫细胞中，我将敲除髓系细胞中的ERα 以确定它是否也是癌症保护所必需的。成功完成这些目标将进一步解释 ER依赖的肺癌保护机制及雌激素和ERα/ERβ的潜在作用 治疗作用。由于STAT3抑制剂的临床试验已经开始，了解性别- 以STAT3为目标的具体结果。我们的结果将指导临床医生通过采取更好的个性化治疗 治疗病人时要考虑到性激素。他们还将阐明抗药性的机制 目前可用的免疫疗法，并提供替代方式。