Mechanistic understanding of the lifecycle of a circulating hybrid cell

对循环混合细胞生命周期的机制理解

基本信息

批准号：
10412136
负责人：
Summer Lynne Gibbs
金额：
$ 62.45万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412136
关键词：
Address Aging Architecture Area Behavioral Binding Sites Biological Biological Assay Biology Blood Circulation Blood specimen Cancer Etiology Cells Cellular biology Cessation of life Clinical Colorectal Cancer Computer Analysis Copy Number Polymorphism DNA Sequence Alteration Development Diagnosis Disease Disseminated Malignant Neoplasm Distant Effector Cell Elements Evaluation Evolution Fluorescence Foundations Gene Expression Human Hybrid Cells Hybrids Immunofluorescence Immunologic Incidence Investigation Knowledge Link Location Malignant Neoplasms Mediating Melissa Micrometastasis Molecular Nature Neoplasm Circulating Cells Neoplasm Metastasis Outcome Patient Care Patients Periodicity Phase Phenotype Population Primary Neoplasm Property Prospective Studies Proteins Publishing Recurrence Reporting Risk Role Sampling Seeds Site Spatial Distribution Technology Testing Therapeutic Time Tumor Biology Tumor stage Work Zebrafish cancer care cohort colon cancer patients falls in vivo innovation insight longitudinal analysis metastatic process migration multidisciplinary multiple omics neoplastic neoplastic cell novel novel strategies peripheral blood stem cells stem-like cell technology development treatment response treatment stratification tumor tumor growth tumor progression

项目摘要

Metastatic disease accounts for >90% of cancer-related deaths worldwide, yet this phase of tumor progression is the least biologically understood. The consequence of this lack of knowledge is that we do not have the appropriate therapeutic arsenal to defeat metastatic cancer. New revelations for colorectal cancer point to shed neoplastic cells into peripheral blood even from early stage tumors, suggesting this is why some early stage tumors recur despite seemingly successful treatment. However, whether all early stage primary tumors shed neoplastic cells, or if only subsets of more aggressive neoplastic cells garner ability to disseminate is not known. This highlights the critical gap in knowledge of the mechanisms underlying neoplastic cell dissemination leading to distant disease. Identifying the key features within the lifecycle of a disseminated tumor cell will unravel this important step in tumor progression with potential to influence management of cancer care. Our study leverages newly developed state-of-the-art phenotypic analyses of key attributes of a recently discovered neoplastic hybrid cell in primary tumors and in peripheral blood, termed circulating hybrid cells (CHCs), supported by cutting-edge computational analyses. Interestingly, CHCs harbor tumor-initiating properties implying that they have high potential as effectors of metastatic tumor seeding. We will detail cells poised to disseminate from the primary tumor into circulation and seed metastatic sites combining protein, multi-omic analyses and functional behavioral analyses. A focus on a stage II and late stage colorectal cancer cohorts support analyses across the disease axis, with an emphasis on stage II CRC patients with undetected micrometastases at the time of diagnoses. Evaluation of the lifecycle of the hybrid cell from primary tumor to dissemination will provide biologic insight into the metastatic process with great potential to impact the management and care of patients with cancer.

转移性疾病占全球癌症相关死亡的90％，但这种肿瘤进展阶段是生物学上最不理解的。缺乏知识的结果是我们没有适当的治疗武器以击败转移性癌症。结直肠癌的新启示指向棚屋肿瘤细胞即使是从早期肿瘤开始进入外周血，这就是为什么一些早期阶段尽管看似成功的治疗，肿瘤也会复发。但是，是否所有早期原发性肿瘤脱落尚不清楚肿瘤细胞，或者只有更具侵略性的肿瘤细胞的子集获得了传播能力。这突出了对肿瘤细胞传播基础机制的知识的关键差距远处疾病。识别传播肿瘤细胞生命周期内的关键特征将揭示此肿瘤进展的重要步骤，可能影响癌症护理的管理。我们的研究利用最近发现的肿瘤混合动力车的关键属性的新开发的最新表型分析原发性肿瘤和外周血中的细胞，称为循环杂种细胞（CHC），由尖端支撑计算分析。有趣的是，CHC藏有肿瘤发射特性，这意味着它们具有很高作为转移性肿瘤播种的效应因子。我们将详细介绍准备从初级传播的单元格肿瘤成循环和种子转移部位，结合蛋白质，多摩变分析和功能性行为分析。重点是II期和晚期结直肠癌队列支持该疾病的分析轴，重点是在诊断时患有未发现微型转移的II期CRC患者。评估从原发性肿瘤到传播的杂交细胞的生命周期将提供生物学洞察力具有影响癌症患者的管理和护理的巨大潜力的转移过程。