The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer

尽管化疗显著提高了乳腺癌患者的生存率，但治疗失败仍然是乳腺癌患者的一个重要因素。 仍然是世界范围内的主要临床问题。目前关于治疗失败的知识主要来自于 上皮性肿瘤细胞内在和获得性耐药的研究。但最近的研究 暗示了宿主细胞的关键作用（即，组织微环境）中建立保护性“生态位”， 肿瘤细胞使其能够逃避化学治疗。值得注意的是，宿主的再生反应 在化疗时，被认为是修复受损组织的宿主内在机制的“损伤”， 被肿瘤细胞利用，用于其局部复发或远处转移。拟议的研究将建立在 我们在乳腺癌转移中肿瘤-间质相互作用研究方面的丰富经验， 研究了化疗诱导的肺间质变化如何促进肺间质的变化这一探索不足的问题。 肺部肿瘤细胞的早期复发。基于我们之前的发现，组织中的间充质干细胞 细胞（MSC）获得显着更高的潜力，以促进局部肿瘤生长后，癌症治疗，我们 假设全身化疗治疗刺激肺驻留MSC的再生反应， 而耐药的播散性肿瘤细胞（DTC）又利用这些细胞在肿瘤细胞中转移复发。 肺。通过在模拟临床情况的动物模型中设计不同的化疗治疗方案， 在人乳腺癌患者中，我们将在目标1中确定化疗药物顺铂和 使用我们新建立的内源性MSC模型， 在小鼠中的平台。随后，我们将在目标2中描述药物活化的分子机制。 肺驻留MSC以支持肺中的转移性肿瘤生长，重点是TLR 4信号传导 途径和关键的伤口愈合细胞因子骨桥蛋白（OPN）。最后，我们将在目标3中定义 使用患者来源的异种移植物模型和乳腺癌模型的基质靶向方法的翻译潜力 癌症患者样本分析。我们将特别关注联合治疗的疗效 TLR 4或OPN阻断化疗治疗患者来源的人基底细胞样异种移植乳腺 肿瘤的此外，通过分析来自人类乳腺癌患者的临床血浆样品，我们期望 开发血浆OPN作为生物标志物，以预测乳腺癌患者术后的早期转移复发。 化疗总的来说，我们提出的研究将振兴一个欠发达的研究领域， 癌症治疗对转移前微环境的影响。拟议研究的结果 将促进临床适用策略的发展，以提高治疗效果和预防 通过干扰组织转移微环境来抑制乳腺癌的转移复发。

Although chemotherapy has significantly improved the survival of breast cancer patients, treatment failure still remains a major clinical issue worldwide. Current knowledge about treatment failure is mostly derived from research on intrinsic and acquired chemoresistance in epithelial tumor cells. However, recent studies have implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response upon chemotherapy “injury”, which is regarded as a host intrinsic mechanism to repair damaged tissues, may be exploited by tumor cells for their local recurrence or distant metastases. The proposed study will build on our extensive experience in the study of tumor-stroma interactions in breast cancer metastasis, and will investigate the poorly explored question of how chemotherapy-induced changes in the lung stroma foster the early relapse of tumor cells in the lung. Based on our previous findings that tissue resident mesenchymal stem cells (MSCs) acquire a significantly higher potential to promote local tumor growth upon cancer therapies, we hypothesize that systemic chemotherapy treatment stimulates regenerative responses in lung resident MSCs, which are, in turn, utilized by drug-resistant disseminated tumor cells (DTCs) for their metastatic relapse in the lung. By designing different chemotherapy treatment scenarios in animal models mimicking clinical situations in human breast cancer patients, we will in Aim 1 determine how chemotherapeutic drugs cisplatin and doxorubicin modulate the lung resident MSCs using our newly established endogenous MSC modeling platform in mice. Subsequently, we will in Aim 2 delineate the molecular mechanisms underlying drug-activated lung resident MSCs to support metastatic tumor growth in the lung, with a focus on the TLR4 signaling pathway and the key wound healing cytokine osteopontin (OPN). Finally, we will in Aim 3 define the translational potential of stroma targeting approaches using both patient-derived xenograft models and breast cancer patient specimen analyses. We will specifically focus on the therapeutic efficacy of combining chemotherapy with TLR4 or OPN blockage in treatment of patient-derived human basal-like xenograft breast tumors. Further, by analyzing clinical plasma samples from human breast cancer patients, we expect to develop plasma OPN as a biomarker to predict early metastatic relapse of breast cancer patients after chemotherapy. Overall, our proposed study will energize an underdeveloped field of research that investigates the impact of cancer therapeutics on the pre-metastatic microenvironment. Findings from the proposed study will facilitate the development of clinically applicable strategies to improve treatment efficacy and prevent metastatic relapse of breast cancer by interfering with the tissue metastatic microenvironment.