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。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的目前局部乳腺肿瘤的治疗标准包括手术、放疗或化疗。虽然化疗可以有效减少甚至消除原发性肿瘤负担，但矛盾的是，促进癌症扩散和转移。了解链接的分子机制针对乳腺癌转移的化疗对于开发更有效的治疗方法至关重要治疗和持久的反应。暴露于化疗或化疗引起的基因毒性应激放射治疗可以导致肿瘤细胞和非转化细胞参与衰老程序相邻的细胞。最近研究表明，衰老细胞的存在会促进攻击性特征癌症肿瘤模型，包括增殖增加、血管生成增强和上皮细胞激活间质转化（EMT）计划。 EMT 赋予癌细胞迁移和侵袭的特征，促进它们从原发肿瘤部位动员并进入循环，有利于转移过程。这衰老细胞分泌一组特定的促炎细胞因子和趋化因子被称为 SASP，被认为可以介导衰老对肿瘤细胞的有害影响。这这项研究的总体目标是利用我们对 SASP 的理解来抑制 SASP 的出现基因毒性治疗后出现侵袭性肿瘤。具体来说，我们将鞭毛蛋白受体 TLR5 鉴定为 siRNA 筛选中衰老驱动的 IL-6 分泌的有效调节剂。我们独立确认了这些结果，并证明 TLR5 耗竭会减弱衰老诱导的多种 SASP 的表达因素。总体而言，TLR5 代表了一个理想的潜在治疗靶点，可以预防 TLR5 的有害影响。接受化疗的乳腺癌患者中的 SASP。我们这里建议确定TLR5的贡献乳腺癌细胞中基因毒性应激诱导的 SASP 产生的信号传导（目标 1），并测试假设阻断 TLR5 信号通路可防止攻击性表型的出现化疗治疗的乳腺癌（目标 2）。该项目的长期目标是发现治疗方法靶向 TLR5 作为预防侵袭性乳腺肿瘤细胞复发的辅助策略的潜力化疗治疗后。