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

摘要 目前治疗区域性乳腺肿瘤的标准包括手术、放射治疗或化疗。 虽然化疗在减轻甚至消除原发肿瘤负担方面是有效的，但矛盾的是，化疗 促进肿瘤扩散和转移。了解连接的分子机制 乳腺癌转移的化疗是提高疗效的关键 治疗和持久的反应。暴露于基因毒性应激，如化疗或 放射治疗可导致肿瘤细胞和非转化细胞参与衰老程序 相邻的细胞。衰老细胞的存在最近被证明促进了攻击性特征 肿瘤模型，包括增殖增加，血管生成增强和上皮细胞激活- 向间充质转化(EMT)计划。EMT赋予癌细胞迁移和侵袭性特征， 促进它们从原发肿瘤部位动员到循环中，有利于转移过程。这个 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，被认为介导了衰老对肿瘤细胞的有害影响。这个 这项研究的总体目标是利用我们对SASP的理解来钝化 基因毒性治疗后的侵袭性肿瘤。具体地说，我们已经确定鞭毛蛋白受体TLR5是 SiRNA筛选中衰老驱动的IL-6分泌的有效调节器。我们独立地证实了这些 结果表明，TLR5的缺失抑制了衰老诱导的多种SASP的表达 各种因素。总体而言，TLR5代表了一个理想的潜在治疗靶点，以防止 SASP在乳腺癌化疗患者中的应用。我们在此建议确定TLR5的贡献 基因毒性应激诱导乳腺癌细胞产生SASP的信号转导(目标1)，并测试 假说阻断TLR5信号通路可防止侵袭性表型的出现 接受化疗的乳腺癌(目标2)。这个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可能性 在化疗之后。

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.