Targeting Oncostatin M-Receptor to Suppress Metastasis and Therapy Failure

靶向制瘤素 M 受体抑制转移和治疗失败

• 批准号: 10364703
• 负责人: MARK W. JACKSON
• 金额: $ 40.46万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-04 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10364703
• 关键词: Binding; Breast Cancer Cell; Breast cancer metastasis; CBL gene; Cell Culture Techniques; Cells; Clinical; Combined Modality Therapy; Complex; Disease; Drug Tolerance; Equilibrium; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Human; Immune; Immune checkpoint inhibitor; Immune system; Immuno-Chemotherapy; Immunosuppressive Agents; Inflammatory; Interferon-beta; Lead; Link; MADH3 gene; Maintenance; Mediating; Mesenchymal; Molecular; Neoplasm Metastasis; Patient-Focused Outcomes; Patients; Phosphorylation; Plant Roots; Population; Production; Recurrence; Recurrent Malignant Neoplasm; Relapse; Repression; Resistance; STAT1 gene; STAT2 gene; STAT3 gene; Seeds; Signal Transduction; Testing; Treatment Failure; Tumor Immunity; Viral; base; cancer cell; cancer cell differentiation; cancer invasiveness; cancer recurrence; chemotherapy; cytokine; immune system function; improved; improved outcome; mimicry; mouse model; nanoparticle; novel; novel therapeutic intervention; oncostatin M; prevent; programs; promoter; receptor; sensor; standard of care; stem; stem-like cell; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

ABSTRACT The metastatic spread of cancer cells and recurrence are intimately linked to therapy failure, which remains an important clinical challenge for patients with metastatic Triple Negative Breast Cancer (TNBC). Two important factors that regulate TNBC metastasis and recurrence are: (i) the differentiation status of the cancer cells, and (ii) the functionality of the immune system within the tumor microenvironment (TME). Both the cancer cells and the immune cells are highly influenced by the cytokines Oncostatin M (OSM) and Interferon-beta (IFNB). We find that the actions of OSM and IFNB oppose one another in regulating both cancer cell differentiation and immune system function within the TME. OSM and its receptor (OSMR) are frequently upregulated in aggressive, metastatic and therapy-resistant recurrent cancers, such as TNBC. Mechanistically, OSM/OSMR elicits robust activation of STAT3, which forms a transcriptional complex with SMAD3, and induces stem-like/mesenchymal programs that enhance TNBC aggressiveness and resistance to chemo- and immuno-therapy. Moreover, the cooperation of STAT3 and SMAD3 on co-dependent gene promoters produces a pro-inflammatory, tumor- promoting TME by suppressing the production of immune-activating IFNB and inducing immune-inhibitory cytokines. Restoring IFNB signaling prevents and reverses stem-like/mesenchymal programming stimulated by OSMR and STAT3/SMAD3. Thus, the cooperation between STAT3 and SMAD3 to inactivate IFNB :STAT1/2 signaling axis represents a key step in metastatic progression and tumor recurrence. Based on these and other compelling findings, we will test the hypothesis that the relative balance between OSM:STAT3/SMAD3 and IFNB :STAT1/2 signaling in both TNBC cells and immune cells dictates metastatic relapse and ultimately, patient outcomes. We’ll test this hypothesis in two Specific Aims: Aim 1 will determine how IFNB suppresses OSMR- mediated STAT3/SMAD3 co-dependent gene expression; Aim 2 will define how OSMR/ERK signaling activates STAT3/SMAD3 to drive stem-like/mesenchymal reprogramming and the suppression of IFNB/ISGs. Together, the results from our studies will provide a greater understanding of the molecular mechanisms by which OSM and IFNB antagonize one another and test novel therapeutic approaches to shift the balance towards active IFNB :STAT1/2 and away from OSMR:STAT3/SMAD3 in both TNBC and immune cells, with the goal of improving outcomes for patients with metastatic TNBC.

抽象的 癌细胞和复发的转移扩散与治疗衰竭密切相关，这仍然是 对转移性三重阴性乳腺癌（TNBC）患者的重要临床挑战。两个很重要 调节TNBC转移和复发的因素是：（i）癌细胞的分化状态，以及 （ii）免疫系统在 肿瘤微环境（TME）。癌细胞和 免疫细胞受到细胞因子oncostatin M（OSM）和干扰素β（IFNB）的高度影响。我们发现 OSM和IFNB的作用在确定癌细胞分化和免疫方面相互反对 TME中的系统功能。 OSM及其受体（OSMR）经常以侵略性更新， 转移和耐药的复发性癌症，例如TNBC。从机械上讲，OSM/OSMR会引起鲁棒 STAT3的激活，形成具有SMAD3的转录复合物，并诱导茎状/间充质 增强TNBC侵略性和对化学和免疫疗法的抵抗力的程序。而且， STAT3和SMAD3在共依赖性基因启动子上的合作产生促炎的肿瘤 通过抑制免疫激活IFNB的产生并诱导免疫抑制作用来促进TME 细胞因子。恢复IFNB信号可防止和逆转茎状/间充质编程，该编程刺激了 OSMR和STAT3/SMAD3。那，STAT3和SMAD3之间的合作使IFNB：STAT1/2 信号轴代表转移性进展和肿瘤复发的关键步骤。基于这些和其他 令人信服的发现，我们将检验以下假设：OSM：STAT3/SMAD3和 IFNB：TNBC细胞和免疫细胞中的STAT1/2信号传导决定转移性继电器，最终患者 结果。我们将以两个具体的目的来检验这一假设：AIM 1将决定IFNB如何抑制OSMR- 介导的STAT3/SMAD3共依赖性基因表达； AIM 2将定义OSMR/ERK信号如何激活 STAT3/SMAD3驱动类茎状/间充质重编程和IFNB/ISGS的抑制。一起， 我们研究的结果将为OSM的分子机制提供更深入的了解 IFNB相互拮抗并测试新颖的治疗方法，将平衡转向主动 IFNB：STAT1/2，远离TNBC和免疫细胞中的OSMR：STAT3/SMAD3，目的是改善 转移性TNBC患者的结局。