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：
10629382
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/10629382
关键词：
Address Aggressive behavior Architecture Area Behavioral Binding Sites Biological Biological Assay Biology Blood specimen Cancer Etiology Cells Cellular biology Cessation of life Circulation Clinical Colorectal Cancer Computer Analysis Copy Number Polymorphism DNA Sequence Alteration Development Diagnosis Disease Disseminated Malignant Neoplasm Distant Effector Cell Elements Evaluation Evolution Foundations Gene Expression Human Hybrid Cells Hybrids Immunofluorescence Immunologic Incidence Investigation Knowledge Life Cycle Stages Link Location Malignant Neoplasms Mediating Micrometastasis Molecular Nature Neoplasm Circulating Cells Neoplasm Metastasis Outcome Patient Care Patients Periodicity Phase Phenotype Population Primary Neoplasm Property Prospective Studies Proteins Publishing Recurrence Recurrent tumor Reporting Risk Role Sampling Site Spatial Distribution Technology Testing Therapeutic Time Tumor Biology Tumor stage Work Zebrafish cancer care cohort colon cancer patients fluorescence imaging in vivo innovation insight longitudinal analysis metastatic process migration multidisciplinary multiple omics neoplastic neoplastic cell novel novel therapeutic intervention peripheral blood protein expression stem cells stem-like cell technology development treatment response treatment stratification tumor tumor growth tumor initiation 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% 以上，但肿瘤进展的这一阶段是生物学上理解最少的。缺乏知识的后果是我们没有能力战胜转移性癌症的适当治疗手段。关于结直肠癌的新发现表明了这一点肿瘤细胞甚至从早期肿瘤进入外周血，这表明这就是为什么一些早期肿瘤尽管看似成功的治疗，肿瘤还是会复发。然而，是否所有早期原发性肿瘤都脱落了？肿瘤细胞，或者是否只有更具侵袭性的肿瘤细胞亚群具有传播能力尚不清楚。这凸显了在肿瘤细胞传播导致的潜在机制知识方面的关键差距到遥远的疾病。识别播散性肿瘤细胞生命周期中的关键特征将解开这个谜团肿瘤进展的重要一步，有可能影响癌症护理的管理。我们的研究利用对最近发现的肿瘤杂种的关键属性进行新开发的最先进的表型分析原发性肿瘤和外周血中的细胞，称为循环杂交细胞（CHC），由尖端技术支持计算分析。有趣的是，CHC 具有肿瘤启动特性，这意味着它们具有高作为转移性肿瘤播种效应器的潜力。我们将详细介绍准备从原代传播的细胞结合蛋白质、多组学分析和功能行为的肿瘤进入循环和种子转移位点分析。对 II 期和晚期结直肠癌队列的关注支持对整个疾病的分析轴，重点关注诊断时未发现微转移的 II 期 CRC 患者。对杂交细胞从原发肿瘤到扩散的生命周期的评估将为以下方面提供生物学见解：转移过程极有可能影响癌症患者的管理和护理。