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.

抽象的 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还要多。而且， 具有 K-ras 驱动突变的肺癌对靶向治疗具有抵抗力。因此，存在未满足的需求 寻找 K-ras 下游的可药物靶标。促进肿瘤的炎症经常由于以下原因发生 K-ras 突变可激活 NF-κB 通路、白细胞介素 6 的产生及其下游的激活 转录因子STAT3。然而，当我们敲除小鼠肿瘤细胞中的 STAT3 时，雌性小鼠的肿瘤细胞中的 STAT3 更少 肿瘤，但男性较多。这种性别差异是由男性中 NF-κB 过度激活造成的，但在女性中， 雌激素信号传导可减少 NF-κB 和促肿瘤炎症。这种保护表型需要 雌激素受体 (ER)，即结合雌激素并与 NF-κB 相互作用的核激素受体。有两个 ER 基因：ERα 和 ERβ。 ERβ 是肺组织中表达的主要 ER 亚型，ERα 主要表达于 免疫细胞。因此，我假设在肺上皮细胞中缺乏 STAT3 的情况下，ERα 和 ERβ 通过抑制 NF-κB 驱动的促肿瘤炎症，信号传导在 K-ras 突变肺癌中具有保护作用。我有两个 检验这一假设的具体目的是针对每个感兴趣的细胞区室的一个目标：肿瘤细胞和 骨髓细胞。目标 1：我将敲除肿瘤中的 ERβ，以确定它是否是女性癌症保护所必需的。 目标2：由于ERα在肿瘤浸润的骨髓免疫细胞中占主导地位，我将敲除骨髓细胞中的ERα 以确定它是否也需要预防癌症。这些目标的成功完成将进一步说明 ER依赖性肺癌保护机制，雌激素和ERα/ERβ发挥新作用的潜力 治疗作用。由于 STAT3 抑制剂的临床试验已经开始，了解性别非常重要 靶向 STAT3 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 治疗患者时要考虑性激素。他们还将阐明抵抗机制 目前可用的免疫疗法并提供替代方式。