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.

摘要 癌细胞的转移扩散和复发与治疗失败密切相关，治疗失败仍然是一种 转移性三阴性乳腺癌患者面临的重要临床挑战。两个重要的因素 调节TNBC转移和复发的因素是：(I)癌细胞的分化状态，以及 (Ii)免疫系统的功能 肿瘤微环境。无论是癌细胞还是 免疫细胞受细胞因子肿瘤抑素M(OSM)和干扰素-β(IFNB)的高度影响。我们发现 OSM和IFNB在调节癌细胞分化和免疫方面的作用相互对立 TME内的系统功能。OSM及其受体(OSMR)在侵袭性、 转移性和耐药复发性癌症，如TNBC。从机制上讲，OSM/OSMR带来了健壮性 激活STAT3，它与Smad3形成转录复合体，诱导干样/间充质形成 增强TNBC侵袭性和对化疗和免疫治疗的抵抗力的计划。此外， STAT3和Smad3在相互依赖的基因启动子上的协同作用产生促炎、肿瘤- 通过抑制免疫激活IFNB的产生和诱导免疫抑制来促进TME 细胞因子。恢复IFNB信号可防止和逆转由 OSMR和STAT3/SMAD3。因此，STAT3和SMAD3之间的合作灭活IFNB：STAT1/2 信号轴是肿瘤转移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OSM：STAT3/SMAD3和OSM：STAT3/SMAD3之间的相对平衡 IFNB：TNBC细胞和免疫细胞中的STAT1/2信号指示转移复发，并最终导致患者 结果。我们将在两个具体目标中检验这一假设：目标1将确定IFNB如何抑制OSMR- 介导的STAT3/SMAD3共同依赖的基因表达；AIM 2将定义OSMR/ERK信号如何激活 STAT3/Smad3驱动茎状/间充质重编程和抑制IFNB/ISGs。一起， 我们的研究结果将使我们对OSM的分子机制有更好的理解 和IFNB相互对抗，并测试新的治疗方法，将平衡转向主动 IFNB：STAT1/2和远离OSMR：STAT3/SMAD3在TNBC和免疫细胞中都是如此，目的是改善 转移性TNBC患者的预后。