Dissecting reciprocal interactions between cancer cells and endothelial cells in SCLC liver metastasis.

项目摘要/摘要 小细胞肺癌(SCLC)是一种顽固性癌症，可导致25万人死亡 每年在全球范围内。小细胞肺癌患者最初对细胞毒治疗有反应，但几乎 难治性疾病总是复发。此外，当确诊时，许多患者都有 包括肝脏在内的远处器官的转移，这是 治疗成功了。转移级联涉及癌细胞与许多正常组织的相互作用 细胞类型，被认为是由促进和抗转移信号提供的。最近的研究表明 研究表明，血管内皮细胞(ECs)在不同肿瘤的转移中发挥着重要而多样的作用。 癌症类型。然而，我们对分子和细胞之间相互作用的理解 小细胞肺癌细胞和内皮细胞在肝转移中仍然不完整，目前还没有预防或 阻止这些相互作用，这标志着小细胞肺癌靶向治疗的巨大可能性 临床上的病人。在这项拟议的研究中，我假设SCLC-EC的相互作用改变了细胞 这两种细胞的状态和这些变化是小细胞肺癌肝转移的关键。至 系统地研究了小细胞肺癌细胞与内皮细胞之间的相互作用。 用于定性记录各种细胞类型之间的物理相互作用的创新方法(GFP- 基于触摸Nexus、G-指挥棒)。与此同时，我导师的实验室已经产生了体细胞 CRISPR基因组编辑小鼠模型及高通量肿瘤条码测序 我将用来解卷转移负荷、转移播种和克隆的平台 小细胞肺癌肝转移中的扩张性。通过利用所有这些尖端技术，该项目 目的通过研究小细胞肺癌活化的内皮细胞在小细胞肺癌肝转移中的作用 CXCLS-CXCR2轴(Aim 1)和其他与细胞间相互作用相关的EC基因的功能 (目标2)。另一方面，该项目还将定量评估EC引发的影响 肝转移中的小细胞肺癌改变(目标3)。综上所述，这个项目将发现新的 对小细胞肺癌转移的机制洞察，建立研究癌症的新策略- 体外和体内的间质相互作用，并确定新的治疗可能性，以更好地治疗 小细胞肺癌患者。

PROJECT SUMMARY / ABSTRACT Small cell lung cancer (SCLC) is a recalcitrant cancer that causes 250,000 deaths worldwide each year. Patients with SCLC initially respond to cytotoxic therapies but almost invariably relapse with therapy resistant disease. Moreover, when diagnosed, many patients have metastases in distant organs including the liver, which represents a major impediment to successful therapy. The metastatic cascade involves cancer cell interactions with many normal cell types, which are thought to provide by pro- and anti-metastatic signals. Recent studies have shown that endothelial cells (ECs) play important and diverse roles in metastasis of different cancer types. However, our understanding of the molecular and cellular interactions between SCLC cells and ECs in liver metastasis remains incomplete and no therapies exist to prevent or stop these interactions, which marks great therapeutic possibilities for target treatment for SCLC patients in clinic. In this proposed study, I hypothesize that SCLC-EC interactions alter the cell state of both cell types and these changes are critical for SCLC liver metastasis. To systemically study the reciprocal interactions between SCLC cells and ECs, I have developed an innovative method to qualitatively record physical interactions between various cell types (GFP- based Touching Nexus, G-baToN). Meanwhile, my mentors' labs have generated somatic CRISPR genome editing mouse models and high-throughput tumor barcode sequencing platforms which I will employ to deconvolute metastatic burden, metastatic seeding, and clonal expansion in SCLC liver metastasis. By leveraging all these cutting-edge techniques, this project aims to characterize the role of SCLC-activated ECs in SCLC liver metastasis through studying the function of the CXCLs-CXCR2 axis (Aim 1) and other cell-cell interaction related EC genes (Aim 2). On the other hand, this project will also quantitatively assess the impact of EC-induced SCLC alternations in liver metastasis (Aim 3). Taken together, this project will uncover new mechanistic insights in SCLC metastasis, establish new strategies for investigating cancer- stromal interactions in vitro and in vivo, and identify new therapeutic possibilities to better treat SCLC patients.