Lung Resident Mesenchymal Cells in the Pre-Metastatic Niche Formation

项目摘要/摘要 转移性疾病仍然是癌症相关死亡的主要原因。在重要的器官中，固体 肿瘤转移，肺部是最常见的之一。肺转移多见于各种晚期 分期为实体癌症，包括乳腺癌。在过去的20年里，肺转移的重大进展 研究揭示了播散性肿瘤细胞(DTC)和肺之间复杂的相互作用 微环境对肺转移性病变的发展至关重要。特别是，形成了 免疫抑制肺转移前微环境(NICE)，这是由分泌的因子驱动的 原发肿瘤，被认为是DTCs到来之前的关键准备阶段。这项提案的重点是 将肺内常驻间充质细胞(MCs)内的一种特征不充分的间质细胞群 肺转移前的壁龛。对小鼠乳腺癌模型的初步研究表明，肺癌患者 MCs通过对不同类型的MCs重新编程，作为免疫抑制转移前利基形成的驱动力 具有高度免疫抑制或耐受性的髓系细胞。这项提议的中心假设是 肺内MCs通过赋予不同的浸润性来驱动肺转移前生态位的形成 具有免疫抑制能力的髓系细胞。要检验这一假说并通过以下方式揭示机制 对于MC对髓系细胞的调控，我们提出了三个具体的目标。目的1：测定肺内残留MC 利用基因操作内源性MC改变肿瘤转移前的生态位。我们会 使用原位乳腺肿瘤细胞移植和基因工程小鼠(GEM)肿瘤模型 检测转移前阶段内源性MC的变化。MCS也将在体内被消融以 确定它们对转移前生态位形成的必要性。目标2：描述关键肺的特征 募集和调节髓系细胞的间质因子。我们将使用RNA测序来分析 转移前肺与正常肺中内源性MC的转录组变化 上调了可能在调节髓系细胞中发挥作用的基因。候选MC基因的贡献 转移前的生态位形成将通过MC特异性基因敲除进行评估。目标3：靶肺 MCS作为临床前取消免疫抑制肺转移前生态位的策略 模特们。利用原位肿瘤移植模型，我们将测试肺MC阻滞剂的能力 增强肺部抗肿瘤免疫，防止肺转移。这些研究将是朝着我们的 全面剖析器官特异性基质细胞在乳腺器官嗜性转移中的作用的长期目标 癌症。我们期待我们的发现将为小说的发展奠定坚实的基础 以基质因子为靶点防治乳腺癌肺转移的治疗策略 癌症和其他实体肿瘤。

PROJECT SUMMARY/ABSTRACT Metastatic disease remains the major cause of cancer-related death. Among the vital organs to which solid tumors metastasize, the lung is one of the most common. Lung metastases frequently occur in various late stage solid cancers including breast cancer. In the past 20 years, significant advances in lung metastasis research have revealed intricate interactions between the disseminated tumor cells (DTCs) and the lung microenvironment that are essential for the development of metastatic lung lesions. In particular, formation of the immunosuppressive lung pre-metastatic microenvironment (niche), which is driven by factors secreted by primary tumors, is regarded as a key preparation stage prior to the arrival of DTCs. The focus of this proposal will be on the lung resident mesenchymal cells (MCs), an under-characterized stromal cell population within the lung pre-metastatic niche. Preliminary studies in mouse models of breast cancer suggest that lung resident MCs serve as a driver of immunosuppressive pre-metastatic niche formation by reprogramming diverse types of myeloid cells to become highly immunosuppressive or tolerogenic. The central hypothesis of this proposal is that lung resident MCs drive formation of the lung pre-metastatic niche by endowing diverse infiltrating myeloid cells with an immunosuppressive capacity. To test this hypothesis and uncover mechanisms by which MCs modulate myeloid cells, we propose three Specific Aims. Aim 1: Determine the lung resident MC changes in the pre-metastatic niche using genetic manipulation of endogenous MCs in mice. We will use orthotopic breast tumor cell implantation and genetically engineered mouse (GEM) tumor models to measure the endogenous MC changes at the pre-metastatic stage. MCs will also be ablated in vivo to determine their necessity for pre-metastatic niche formation. Aim 2: Characterize the key lung mesenchymal factors that recruit and modulate myeloid cells. We will use RNA sequencing to profile transcriptome changes between endogenous MCs residing in pre-metastatic vs. normal lungs to identify upregulated genes that might play a role in modulating myeloid cells. The contribution of candidate MC genes to pre-metastatic niche formation will be evaluated through MC-specific gene knockout. Aim 3: Target lung MCs as a strategy for abolishing the immunosuppressive lung pre-metastatic niche in preclinical models. Using orthotopic tumor implantation models, we will test the ability of lung MC blockade agents to boost lung anti-tumor immunity and prevent lung metastasis. These studies will be a significant step toward our long-term goal to fully dissect the roles of organ-specific stromal cells in organ-tropic metastases of breast cancer. We anticipate that our findings will establish a strong foundation for the development of novel therapeutic strategies that target stromal factors for the prevention and treatment of lung metastases of breast cancer and other solid tumors.