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Investigation of heterogeneity in cancer cell proliferation.

癌细胞增殖异质性的研究。

基本信息

批准号：
10642709
负责人：
Stefan Ross Torborg
金额：
$ 5.27万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642709
关键词：
3-Dimensional Acyltransferase Adenocarcinoma Cell Allografting Automobile Driving Basic Science Behavior Biological Assay Biology CRISPR/Cas technology Cancer Etiology Cell Proliferation Cell Separation Cell division Cells Cessation of life Chimeric Proteins Clinical Colon Carcinoma Complex DNA Repair Data Disease Disease Outcome Doxycycline Drug Efflux Enterobacteria phage P1 Cre recombinase Flow Cytometry Future Gene Expression Profile Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Heterogeneity High Prevalence Histologic Histones Individual Information Theory Investigation Knock-out Label Lentivirus Vector Ligands Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of prostate Measures Medicine Methods Mus Mutation Neoplasm Metastasis Organoids Oxidative Stress Pathway interactions Patients Phenotype Population Porcupines Prevalence Prognosis Proliferating Property Publishing Relapse Renal carcinoma Research Resistance Role Sorting Survival Rate System Testing Therapeutic Tissues Transplantation Treatment Failure Tumor Tissue Up-Regulation WNT Signaling Pathway Wnt proteins Work cancer cell cancer stem cell cancer therapy cancer type cell growth effective therapy efflux pump experimental study improved in vivo malignant breast neoplasm mortality mouse model novel prevent refractory cancer resilience single cell mRNA sequencing small hairpin RNA stem stem cells stem-like cell stemness targeted cancer therapy therapeutic target tumor tumor behavior tumor growth tumor heterogeneity tumor progression tumorigenic vector

项目摘要

Project Summary/Abstract Lung adenocarcinoma is a complex disease with high prevalence and mortality. The low survival rate is worsened by the long-term ineffectiveness of many cancer therapeutics, which eliminate most but not all of the cancer cells in a tumor. Cellular phenotypic diversity is an important feature of cancer for the fields of basic biology and medicine, but the mechanisms by which tumors establish and maintain this diversity is poorly understood. One key aspect of tumor phenotypic diversity is proliferative heterogeneity: the presence of cancer cells that exist in proliferative states ranging from quiescence to persistent cell division. The Wnt pathway is a potentially important driver of proliferative heterogeneity, as it is central to the maintenance of a highly proliferative, cancer stem cell- like state in lung adenocarcinoma. To interrogate proliferative heterogeneity in an unbiased manner, we have established a novel genetically engineered mouse model of lung adenocarcinoma that enable us to identify different tumor subpopulations based on proliferative state. We will use this mouse model to isolate highly proliferative and persistently quiescent cancer cells, which we will then interrogate functionally and transcriptionally. In these experiments we seek to identify the impact of a cell’s proliferative state on its tumorigenic capacity (Aim 1). We will also characterize the mechanisms by which distinct proliferative states are established and maintained. In particular, we will focus on the Wnt pathway to identify the role of individual Wnt ligands in driving distinct proliferative states. The goal of these experiments is to determine the impact of targeting Wnt signaling on specific proliferative states and to identify additional cell states with robust growth potential (Aim 2). Lung cancer has a poor prognosis, but basic science research that improves the understanding of lung tumor heterogeneity can lead to significant advancements in how patients are treated. Further elucidating the phenotypic diversity that causes disease relapses may advance our ability to control tumor behavior and increase the ability of existing cancer treatments to fully eradicate the disease through elimination of resistant cell states.

项目摘要/摘要肺腺癌是一种发病率高、死亡率高的复杂疾病。低存活率进一步恶化由于许多癌症疗法长期无效，它们消灭了大部分但不是所有的癌细胞在肿瘤里。细胞表型多样性是癌症的一个重要特征，在基础生物学和医学，但肿瘤建立和维持这种多样性的机制知之甚少。一肿瘤表型多样性的关键方面是增殖的异质性：存在于从静止到持续的细胞分裂的增殖状态。Wnt途径是一个潜在的重要途径增殖异质性的驱动力，因为它是维持高度增殖的癌症干细胞的核心- 类似肺腺癌的状态。为了以公正的方式审问增殖性异质性，我们有建立了一种新的肺腺癌基因工程小鼠模型，使我们能够识别基于增殖状态的不同肿瘤亚群。我们将使用这个小鼠模型来分离高度增殖和持续静止的癌细胞，然后我们将对其进行功能和从转录上讲。在这些实验中，我们试图确定细胞的增殖状态对其致瘤能力(目标1)。我们还将描述不同的增殖状态的机制建立和维护。我们将特别关注WNT途径，以确定单个WNT的作用驱动不同增殖状态的配体。这些实验的目标是确定靶向的影响 WNT在特定的增殖状态上的信号转导，并识别具有强大生长潜力的其他细胞状态 (目标2)。肺癌的预后很差，但基础科学研究提高了对肺的认识肿瘤的异质性可以导致患者治疗方式的显著进步。进一步澄清导致疾病复发的表型多样性可能会提高我们控制肿瘤行为的能力，并增加现有癌症治疗方法通过消除耐药细胞状态来完全根除疾病的能力。