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

肺驻留间充质干细胞在乳腺癌化疗后肺转移中的作用

• 批准号: 9885667
• 负责人: Guangwen Ren
• 金额: $ 40.03万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-04 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885667
• 关键词: Animal Model; Biological Markers; Biological Models; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; CD44 gene; Cancer Patient; Cell Proliferation; Cells; Cessation of life; Cisplatin; Clinical; Development; Disease remission; Distant; Distant Metastasis; Doxorubicin; Drug Utilization; Drug resistance; Endothelial Cells; Epithelial; Epithelium; Failure; Fostering; Foundations; Gene Expression; Goals; Human; Immune response; Inflammation; Injury; Knowledge; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Mesenchymal; Mesenchymal Stem Cells; Metastatic Neoplasm to the Lung; Metastatic to; Molecular; Mus; Myofibroblast; Natural regeneration; Neoplasm Metastasis; Organ; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Play; Population; Recurrence; Regenerative response; Relapse; Research; Resistance; Respiratory physiology; Role; Sampling; Signal Pathway; Specimen; Stromal Cells; TLR4 gene; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment Failure; Xenograft procedure; acquired drug resistance; base; bone; breast cancer survival; cancer therapy; chemotherapy; clinical application; clinical development; cytokine; cytotoxicity; design; endothelial stem cell; experience; improved; insight; lung metastatic; malignant breast neoplasm; neoplastic cell; novel; novel strategies; osteopontin; pre-clinical; prevent; repaired; response; stem cell model; therapeutic target; therapy resistant; tissue injury; tumor; tumor growth; wound healing

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.

尽管化疗显着提高了乳腺癌患者的生存率，但治疗失败仍然存在 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源于 上皮肿瘤细胞内在和获得性化疗耐药性的研究。然而，最近的研究表明 暗示宿主细胞（即组织微环境）在建立保护性“生态位”方面发挥着关键作用 肿瘤细胞使其能够逃避化疗。值得注意的是，宿主的再生反应 化疗“损伤”被认为是修复受损组织的宿主内在机制，可能 被肿瘤细胞利用以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-基质相互作用研究方面拥有丰富的经验，并将 研究化疗引起的肺基质变化如何促进 肺部肿瘤细胞早期复发。根据我们之前的发现，组织驻留间充质干 细胞（MSC）在癌症治疗后具有显着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驻留间充质干细胞的再生反应， 反过来，它们又被耐药播散性肿瘤细胞（DTC）利用，用于治疗肿瘤的转移复发。 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 阿霉素使用我们新建立的内源性 MSC 模型调节肺驻留 MSC 小鼠平台。随后，我们将在目标 2 中描述药物激活的分子机制。 肺驻留 MSC 支持肺部转移性肿瘤生长，重点关注 TLR4 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模型和乳房的基质靶向方法的转化潜力 癌症患者样本分析。我们将特别关注联合治疗的治疗效果 TLR4 或 OPN 阻断化疗治疗患者来源的人基底细胞样异种移植乳房 肿瘤。此外，通过分析人类乳腺癌患者的临床血浆样本，我们期望 开发血浆 OPN 作为生物标志物来预测乳腺癌患者术后早期转移复发 化疗。总的来说，我们提出的研究将为一个不发达的研究领域注入活力，该领域调查 癌症治疗对转移前微环境的影响。拟议研究的结果 将促进临床适用策略的开发，以提高治疗效果并预防 通过干扰组织转移微环境来抑制乳腺癌转移复发。