The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis

摘要 肺癌仍然是全球癌症相关死亡的主要原因。虽然靶向治疗针对 致癌驱动因子和免疫治疗方法已经显示出在降低肿瘤的发病率、对肿瘤的耐药性、以及对肿瘤的治疗方面的前景。 靶向治疗常常导致疾病的复发和进展。此外，只有一小部分 的非小细胞肺癌（NSCLC）患者对单一免疫疗法有反应。因此，小说 迫切需要治疗方法。开发新的治疗策略需要更好的 了解癌细胞和肿瘤微环境中细胞之间的复杂相互作用 （TME）。TME是多种细胞类型的复杂生态位，包括先天性和适应性免疫细胞。 免疫系统、癌症相关的成纤维细胞、血管细胞和细胞外基质（ECM）。定义 TME细胞调节癌症进展的关键细胞类型和机制仍然是一个挑战。 最近出现了大量与募集的免疫细胞相关的研究。此外，虽然肿瘤 血管生成是癌症的标志，抗血管生成疗法在治疗肺癌方面的成功有限。 因此，需要更好地了解血管系统如何促进疾病进展。 最后，虽然癌症干细胞在癌症进展中的作用已经得到很好的确立，但基质干细胞在癌症进展中的作用还有待进一步研究。 促进TME和癌症进展和转移的祖细胞/干细胞是一种完全的免疫调节剂。 未被充分研究的领域。我们通过使用命运测绘系统进行的偶然观察 在血管疾病背景下追踪血管平滑肌细胞（SMC）的研究表明，成熟的SMC 迁移到血管的外膜层并被遗传重编程为亚群 称为AdvSca 1-SM细胞的常驻外膜祖细胞。AdvSca 1-SM细胞是一个选择的亚群 真正的血管祖细胞，表现出多种命运决定。AdvSca 1-SM细胞位于多个 血管床（例如，主动脉、颈动脉和股动脉以及肺动脉和冠状动脉脉管系统）。 重编程依赖于SMC对转录因子Klf 4的诱导，而AdvSca 1-SM细胞是重编程细胞。 主要的细胞类型响应于血管壁功能障碍，其依赖于Klf 4的损失。我们最近 研究结果表明，肺AdvSca 1-SM细胞数量增加，采用肌成纤维细胞表型， 是肺癌进展和转移的主要因素。我们在这里提出，癌细胞介导的 AdvSca 1-SM细胞的活化导致其分化为TME的必需细胞， 进展和转移。消融将使肿瘤变钝，但Klf 4表达的丧失将加剧肿瘤生长， 转移两个目标将检验我们的假设。目的一将使用创新的体内命运映射和体外 条件培养基方法来确定AdvSca 1-SM细胞的命运和癌细胞在AdvSca 1-SM中的作用。 肺癌进展和转移背景下的SM细胞活化。目标二将确定 AdvSca 1-SM细胞消融或AdvSca 1-SM特异性Klf 4缺失对肺癌进展和转移的影响

ABSTRACT Lung cancer remains the leading cause of cancer-related deaths worldwide. While targeted therapies against oncogenic drivers and immunotherapy approaches have shown promise in reducing the incidence, resistance to targeted therapies often leads to relapse and progression of disease. In addition, only a relatively small portion of unselected non-small cell lung cancer (NSCLC) patients respond to mono-immunotherapy. Therefore, novel therapeutic approaches are urgently needed. Developing new therapeutic strategies requires a better understanding of the complex interactions between cancer cells and cells within the tumor microenvironment (TME). The TME is a complex niche of multiple cell types, including immune cells of the innate and adaptive immune system, cancer-associated fibroblasts, vascular cells, and extracellular matrix (ECM). Defining the critical cell types and mechanisms whereby cells of the TME regulate cancer progression remains a challenge. Recently an abundance of studies related to recruited immune cells have emerged. Also, while tumor angiogenesis is a hallmark of cancer, anti-angiogenic therapy has had limited success for the treatment of lung cancer, and thus a better understanding of how the vasculature contributes to disease progression is required. Finally, while the role of cancer stem cells to cancer progression has been well established, the role of stromal progenitor/stem cells contributing to the TME and cancer progression and metastasis is a completely understudied area of research. Serendipitous observations made by us through the use of fate-mapping systems to track vascular smooth muscle cells (SMCs) in the setting of vascular disease demonstrated that mature SMCs migrate into the outer adventitial layer of the blood vessel and are genetically reprogrammed into a subpopulation of resident adventitial progenitor cells termed AdvSca1-SM cells. AdvSca1-SM cells are a select subpopulation of authentic vascular progenitor cells that exhibit multiple fate decisions. AdvSca1-SM cells reside in multiple vascular beds (e.g. aorta, carotid and femoral arteries, and the pulmonary and coronary arterial vasculature). Reprogramming is dependent on SMC induction of the transcription factor, Klf4, and AdvSca1-SM cells are the predominant cell type responding to vessel wall dysfunction, which is dependent on loss of Klf4. Our recent findings demonstrate that lung AdvSca1-SM cells expand in number, adopt a myofibroblast phenotype, and are major contributors to lung cancer progression and metastasis. We propose here that cancer cell-mediated activation of AdvSca1-SM cells results in their differentiation into essential cells of the TME that promote tumor progression and metastasis. Ablation will blunt, but loss of Klf4 expression will exacerbate tumor growth and metastasis. Two Aims will test our hypotheses. Aim One will use innovative in vivo fate mapping and in vitro conditioned media approaches to define the fate of AdvSca1-SM cells and the role of cancer cells in AdvSca1- SM cell activation in the setting of lung cancer progression and metastasis. Aim Two will define the role of AdvSca1-SM cell ablation or AdvSca1-SM-specific deletion of Klf4 on lung cancer progression and metastasis.