Mechanisms of Neoplastic Hybrid Cell Dissemination in Colorectal Cancer

项目摘要 转移性疾病是癌症发病率和死亡率的主要原因，导致1000万人死亡。 2020年在全球范围内。尽管我们对转移性肿瘤发展的了解最近取得了进展，但仍有一个关键的 需要了解离散的肿瘤细胞亚群成功的分子机制 进入循环，以改进监测和减少转移性疾病负担的战略。我们的团队 发现一种独特的播散性肿瘤细胞亚型，其特征是肿瘤和 可由肿瘤-巨噬细胞融合形成的免疫细胞基因型别和表型。这些混血儿 外周血中发现的细胞比其他循环中的肿瘤来源细胞(CTCs)的数量更多 表现出更强的迁移和侵袭潜力，以及在转移部位种植和扩张的能力 费率高于CTC。然而，杂交细胞做到这一点的机制目前尚不清楚。在我的 杂交细胞基因表达的初步分析--从Run相关基因中鉴定上调成分 杂交细胞中转录因子1(RUNX1)途径与肿瘤细胞的比较。RUNX1是一种转录因子 它调节造血干细胞分化和巨噬细胞迁移，并已被证明在 通过促进结直肠癌上皮向间充质转化促进肿瘤细胞的转移转化。在一个 杂交细胞RUNX1可以将巨噬细胞和肿瘤细胞的功能行为整合到一个单一的 并为它们的成功传播提供便利。因此，我假设散布的亚群 肿瘤杂交细胞显示差异RUNX1冥想~组学和功能表达，促进 增强了肿瘤的扩散。 该项目建议首先评估大肠杂交细胞的基因表达和表型特征。 肿瘤与外周血混合细胞的特性鉴定成功扩散。 此外，该项目将评估RUNX1在促进增强的杂交细胞迁移方面的功能作用 和传播。这些研究的成功完成将确定肿瘤的分子基础 杂交细胞的迁移和扩散，将为未来探索这种独特的肿瘤提供基础 亚型作为检测早期转移疾病和肿瘤演变的生物标志物。 此外，这项申请提出了一个全面的和跨学科的培训计划在一个突出的 与研究提案无缝集成的学术医疗和研究机构，提供 系统和分子癌症生物学方面的基本培训，以支持候选人的职业目标 作为内科科学家的学术翻译肿瘤学实验室。

Project Summary Metastatic disease is the primary cause of cancer morbidity and mortality, resulting in >10 million deaths worldwide in 2020. Despite recent advances in our knowledge of metastatic tumor development, there is a critical need to understand the molecular mechanisms by which discrete subpopulations of neoplastic cells successfully enter circulation to improve strategies for monitoring and reducing metastatic disease burden. Our team discovered a unique disseminated neoplastic cell subtype characterized by co-expression of neoplastic and immune cell genotypes and phenotypes that can form from neoplastic-macrophage cell fusion. These hybrid cells are found in peripheral blood at numbers greater than other circulating tumor-derived cells (CTCs) and exhibit increased migratory and invasive potential as well as the ability to seed and expand at metastatic sites at rates greater than CTCs. However, the mechanisms by which hybrid cells do so is currently unknown. In my preliminary analyses of hybrid cell gene expression, I identified upregulated components from the Runt-related transcription factor 1 (RUNX1) pathway in hybrid cells compared to tumor cells. RUNX1 is a transcription factor that regulates hematopoietic stem cell differentiation and macrophage migration and has been shown to mediate metastatic conversion of tumor cells by facilitating epithelial-to-mesenchymal transition in colorectal cancer. In a hybrid cell, RUNX1 may integrate the functional behaviors of both macrophages and tumor cells into a single cell and facilitate their successful dissemination. Therefore, I hypothesize that disseminated subpopulations of neoplastic hybrid cells display differential RUNX1 meditated ~omics and functional expression that facilitates enhanced tumor dissemination. This project proposes to first assess the gene expression and phenotypic profiles of hybrid cells in colorectal cancer tumors and peripheral blood to identify characteristics of hybrid cells that successfully disseminate. Additionally, this project will evaluate the functional role of RUNX1 in facilitating enhanced hybrid cell migration and dissemination. Successful completion of these studies will define the molecular underpinnings of neoplastic hybrid cell migration and dissemination and will provide the basis for future exploration of this unique neoplastic subtype as a biomarker for the detection of early metastatic disease and tumor evolution. Furthermore, this application proposes a comprehensive and interdisciplinary training plan within a prominent academic medical and research institution that seamlessly integrates with the research proposal, providing essential training in systems and molecular cancer biology to support the candidates career goal of maintaining an academic translational oncology laboratory as a physician scientist.