Mechanisms of Neoplastic Hybrid Cell Dissemination in Colorectal Cancer

结直肠癌中肿瘤性杂交细胞播散的机制

基本信息

批准号：
10462423
负责人：
Ashley Nicole Anderson
金额：
$ 3.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2026-09-07
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10462423
关键词：
3-Dimensional Accounting Behavior Blood Circulation Cancer Biology Cancer Etiology Cell Culture Techniques Cell fusion Cells Cessation of life Characteristics Colorectal Cancer Data Development Disease Distant Epigenetic Process Evaluation Evolution Exhibits Foundations Future Gene Expression Genes Genotype Goals Heterogeneity Hybrid Cells Hybrids Immune Immune Tolerance Immunofluorescence Immunologic In Vitro Institution Investigation Knock-out Knowledge Label Laboratories Large Intestine Carcinoma Malignant Neoplasms Mediating Medical Research Methods Migration Assay Molecular Monitor Morbidity - disease rate Neoplasm Circulating Cells Neoplasm Metastasis Organ Pathway interactions Patients Periodicity Phenotype Physicians Population Primary Neoplasm Property RUNX1 gene Research Research Proposals Role Sampling Scientist Seeds Site System Tissue-Specific Gene Expression Training Tumor-Derived Validation Work Xenograft procedure Zebrafish acute myeloid leukemia 1 protein base burden of illness cancer type career cell motility early detection biomarkers epithelial to mesenchymal transition hematopoietic stem cell differentiation hybrid gene improved in vivo in vivo Model innovation live cell imaging lymphatic vessel mRNA Differential Displays macrophage migration mortality neoplastic neoplastic cell novel peripheral blood peripheral blood vessel prevent protein expression single-cell RNA sequencing therapeutic target transcription factor translational oncology tumor tumor microenvironment tumor progression

项目摘要

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.

项目概要转移性疾病是癌症发病率和死亡率的主要原因，导致超过 1000 万人死亡 2020 年全球范围内。尽管我们对转移性肿瘤发展的了解最近取得了进展，但仍有一个关键问题需要了解肿瘤细胞离散亚群成功的分子机制进入循环系统以改善监测和减少转移性疾病负担的策略。我们的团队发现了一种独特的播散性肿瘤细胞亚型，其特征是肿瘤细胞和肿瘤-巨噬细胞融合形成的免疫细胞基因型和表型。这些混合体外周血中发现的细胞数量多于其他循环肿瘤衍生细胞 (CTC)，并且表现出增加的迁移和侵袭潜力以及在转移位点播种和扩展的能力率高于 CTC。然而，杂交细胞这样做的机制目前尚不清楚。在我的通过对杂交细胞基因表达的初步分析，我从 Runt 相关的与肿瘤细胞相比，杂交细胞中的转录因子 1 (RUNX1) 通路。 RUNX1 是一种转录因子调节造血干细胞分化和巨噬细胞迁移，并已被证明可以介导通过促进结直肠癌的上皮到间质转化来实现肿瘤细胞的转移转化。在一个作为杂交细胞，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细胞中。细胞并促进其成功传播。因此，我假设传播的亚群肿瘤杂交细胞表现出差异的 RUNX1 介导的组学和功能表达，有助于增强肿瘤播散。该项目建议首先评估结直肠杂交细胞的基因表达和表型特征癌症肿瘤和外周血，以确定成功传播的杂交细胞的特征。此外，该项目将评估 RUNX1 在促进增强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迁移和传播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性疾病和肿瘤进化的生物标志物。此外，该应用程序在突出的范围内提出了全面的跨学科培训计划与研究计划无缝结合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必要培训，以支持候选人维持职业目标作为医师科学家的学术转化肿瘤学实验室。