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

项目摘要/摘要 虽然化疗显著提高了乳腺癌患者的存活率，但治疗仍然失败 仍然是世界范围内的一个主要临床问题。目前关于治疗失败的知识主要来自于 上皮性肿瘤细胞固有和获得性耐药的研究。然而，最近的研究表明 暗示宿主细胞(即组织微环境)在为 肿瘤细胞使它们能够逃脱化疗治疗。值得注意的是，宿主的再生反应 在化疗中，“损伤”被认为是修复受损组织的宿主内在机制，可能 被肿瘤细胞利用来进行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，并将 对化疗引起的肺间质改变如何促进肺间质生长这一鲜为人知的问题进行调查。 肺部肿瘤细胞的早期复发。根据我们之前的发现，组织驻留的间充质干细胞 细胞(MSCs)在癌症治疗中获得了显著更高的促进局部肿瘤生长的潜力，我们 假设全身化疗刺激肺内MSCs的再生反应， 它们反过来又被耐药的播散性肿瘤细胞(DTC)利用，用于它们在 阿龙。通过在模拟临床情况的动物模型中设计不同的化疗方案 在人类乳腺癌患者中，我们将在目标1中确定化疗药物顺铂和 用我们新建立的内源性MSCs模型研究阿霉素对肺内MSCs的调节作用 在小鼠身上站台。随后，我们将在目标2中描述药物激活的分子机制。 肺内MSCs支持肺转移瘤生长，重点是TLR4信号转导 创伤修复的关键细胞因子骨桥蛋白(OPN)及其途径。最后，我们将在目标3中定义 使用患者来源的异种移植模型和乳房的基质靶向方法的翻译潜力 癌症患者标本分析。我们将特别关注中西医结合的治疗效果 TLR4或OPN阻断化疗治疗人基底样异种移植乳腺 肿瘤。此外，通过分析人类乳腺癌患者的临床血浆样本，我们希望 将血浆骨桥蛋白作为预测乳腺癌术后早期转移复发的生物标志物 化疗。总体而言，我们提议的研究将激励一个不发达的研究领域，即调查 癌症治疗对转移前微环境的影响。拟议研究的结果 将促进制定临床适用的策略，以提高治疗效果和预防 干扰组织转移微环境的乳腺癌转移复发。

PROJECT SUMMARY/ABSTRACT 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.