Targeting the HMGB1-TLR5 pathway to prevent senescence-induced metastasis in breast cancer.

靶向 HMGB1-TLR5 通路预防乳腺癌衰老诱导的转移。

• 批准号: 10599637
• 负责人: Gregory David
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599637
• 关键词: Adjuvant; Adverse effects; Affect; Binding; Biological; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Prevention; Cell Aging; Cell Cycle; Cell Survival; Cell model; Cells; Circulation; Cytotoxic Chemotherapy; DNA Damage; Data; Development; Disease; Exposure to; Flagellin; Genetic; Genotoxic Stress; Goals; HMGB1 gene; Human; IL-6 inhibitor; IL8 gene; In Vitro; Inflammatory; Inflammatory Response; Interleukin-6; Invaded; Light; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metalloproteases; Metastasis Induction; Modeling; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Normal Cell; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Primary Neoplasm; Production; Proliferating; Property; Radiation therapy; Relapse; Sampling; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stress; TLR5 gene; Testing; Therapeutic; Toll-like receptors; Tumor Burden; Withholding Treatment; Woman; aggressive breast cancer; angiogenesis; breast cancer progression; cancer cell; cancer therapy; chemokine; chemotherapy; cytokine; cytotoxic; effective therapy; epithelial to mesenchymal transition; extracellular; genotoxicity; malignant breast neoplasm; metastatic process; migration; mouse model; neoplastic cell; novel therapeutics; pharmacologic; prevent; programs; response; senescence; standard care; therapeutic target; trait; tumor; tumor microenvironment; tumor progression

ABSTRACT The current standard for treatment of regional breast tumors involves surgery, radiotherapy or chemotherapy. While effective at reducing or even eliminating the primary tumor burden, chemotherapy can paradoxically promote cancer dissemination and metastasis. Understanding the molecular mechanisms that link chemotherapeutic treatment to metastasis in breast cancer is paramount to developing more effective treatments and a durable response. Exposure to genotoxic stress, as elicited upon chemotherapy or radiotherapy, can result in the engagement of a senescence program in both tumor cells and non-transformed neighboring cells. The presence of senescent cells has recently been shown to promote aggressive traits in cancer tumor models, including increased proliferation, enhanced angiogenesis and activation of the epithelial- to-mesenchymal transition (EMT) program. EMT confers migratory and invasive features to cancer cells, which facilitate their mobilization out of primary tumor sites and into circulation, favoring the metastatic process. The secretion by senescent cells of a specific set of proinflammatory cytokines and chemokines, collectively referred to as the SASP, is believed to mediate the detrimental effects of senescence on tumor cells. The overarching goal of this study is to leverage our understanding of the SASP to blunt the emergence of aggressive tumors following genotoxic treatment. Specifically, we have identified the flagellin receptor TLR5 as a potent regulator of senescence-driven IL-6 secretion in an siRNA screen. We independently confirmed these results, and demonstrated that TLR5 depletion blunts senescence-induced expression of diverse SASP factors. Overall, TLR5 represents an ideal potential therapeutic target to prevent the detrimental effects of the SASP in chemotherapy-treated breast cancer patients. We propose here to determine the contribution of TLR5 signaling to genotoxic stress-induced SASP production in breast cancer cells (aim 1), and to test the hypothesis that blocking the TLR5 signaling pathway prevents the emergence of aggressive phenotypes in chemotherapy-treated breast cancer (aim 2). The long-term goal of this project is to uncover the therapeutic potential of targeting TLR5 as an adjuvant strategy to prevent the resurgence of aggressive breast tumor cells following chemotherapy treatment.

抽象的 当前治疗区域乳腺肿瘤的标准涉及手术，放疗或化学疗法。 虽然有效减少甚至消除了原发性肿瘤负担，但化学疗法可以自相矛盾 促进癌症传播和转移。了解连接的分子机制 乳腺癌转移的化学治疗方法对于发展更有效至关重要 治疗和持久的反应。在化学疗法或 放疗，可能导致衰老程序在肿瘤细胞和未转化 相邻的细胞。最近已显示出衰老细胞的存在可促进侵略性特征 癌症肿瘤模型，包括增加增殖，增强的血管生成和上皮的激活 待机质转换（EMT）程序。 EMT赋予癌细胞的迁移和侵入性特征，这些特征 有利于转移过程，促进其动员从原发性肿瘤部位移动并循环。这 衰老细胞分泌一组特定的促炎细胞因子和趋化因子，共同分泌 据信被称为SASP，可以介导衰老对肿瘤细胞的有害作用。这 这项研究的总体目标是利用我们对SASP的理解来钝化 遗传毒性治疗后的侵袭性肿瘤。具体而言，我们已经将鞭毛蛋白受体TLR5确定为 在siRNA屏幕中，由衰老驱动的IL-6分泌的有效调节剂。我们独立证实了这些 结果，并证明TLR5耗尽钝性会导致衰老诱导的SASP表达 因素。总体而言，TLR5代表了防止有害影响的理想潜在治疗靶标 SASP在化学治疗治疗的乳腺癌患者中。我们在这里建议确定TLR5的贡献 向遗传毒性应激诱导的乳腺癌细胞中SASP产生的信号传导（AIM 1），并测试 阻止TLR5信号通路的假设阻止了侵略性表型的出现 化学治疗治疗的乳腺癌（AIM 2）。该项目的长期目标是发现治疗性 将TLR5作为防止侵袭性乳腺肿瘤细胞复发的辅助策略的潜力 化学疗法治疗后。