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

摘要 目前治疗局部乳腺肿瘤的标准包括手术、放疗或化疗。 化疗虽然能有效减少甚至消除原发肿瘤负荷，但矛盾的是， 促进癌症的扩散和转移。了解分子机制， 乳腺癌转移的化学治疗对于开发更有效的 治疗和持久的反应。暴露于遗传毒性应激，如化疗或 放射治疗，可以导致肿瘤细胞和非转化细胞中衰老程序的参与。 相邻的细胞。衰老细胞的存在最近已被证明促进了攻击性特征， 癌症肿瘤模型，包括增加的增殖，增强的血管生成和上皮细胞的激活， 向间充质转化（EMT）计划。EMT赋予癌细胞迁移和侵袭特征， 促进它们从原发肿瘤部位动员出来并进入循环，有利于转移过程。的 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，被认为介导衰老对肿瘤细胞的有害作用。的 这项研究的首要目标是利用我们对SASP的理解来削弱 遗传毒性治疗后的侵袭性肿瘤。具体地说，我们已经鉴定了鞭毛蛋白受体TLR 5， siRNA筛选中衰老驱动的IL-6分泌的有效调节剂。我们独立证实了这些 结果，并证明TLR 5耗竭减弱衰老诱导的多种SASP表达， 因素总之，TLR 5代表了一种理想的潜在治疗靶点，以防止TLR 5的有害作用。 化疗治疗的乳腺癌患者中的SASP。我们在这里建议确定TLR 5的贡献， 在乳腺癌细胞中基因毒性应激诱导的SASP产生的信号传导（目的1），并测试 阻断TLR 5信号通路可以防止侵袭性表型的出现， 化疗治疗的乳腺癌（目标2）。这个项目的长期目标是揭示治疗 靶向TLR 5作为预防侵袭性乳腺肿瘤细胞复发的辅助策略的潜力 在化疗后。

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.