Investigation of heterogeneity in cancer cell proliferation.

癌细胞增殖异质性的研究。

• 批准号: 10434832
• 负责人: Stefan Ross Torborg
• 金额: $ 5.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434832
• 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 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; Genetic Transcription; Genetically Engineered Mouse; Goals; Growth; Heterogeneity; High Prevalence; Histologic; Histones; Individual; Information Theory; Investigation; Knock-out; Label; Lead; 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; Recurrent disease; Relapse; Renal carcinoma; Research; Resistance; Role; Survival Rate; Testing; Therapeutic; Tissues; Transplantation; Tumor Tissue; Up-Regulation; WNT Signaling Pathway; Wnt proteins; Work; base; 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

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.

项目概要/摘要 肺腺癌是一种发病率和死亡率较高的复杂疾病。低生存率进一步恶化 由于许多癌症疗法长期无效，这些疗法消除了大部分但不是全部癌细胞 在肿瘤中。细胞表型多样性是基础生物学和癌症领域的一个重要特征 但人们对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异质性：存在于肿瘤细胞中的癌细胞的存在 增殖状态范围从静止到持续细胞分裂。 Wnt 通路是一个潜在的重要通路 增殖异质性的驱动因素，因为它对于维持高度增殖的癌症干细胞至关重要 类似肺腺癌的状态。为了以公正的方式询问增殖异质性，我们有 建立了一种新型基因工程小鼠肺腺癌模型，使我们能够识别 基于增殖状态的不同肿瘤亚群。我们将使用该小鼠模型来高度分离 增殖且持续静止的癌细胞，然后我们将对其进行功能性检查并 转录地。在这些实验中，我们试图确定细胞的增殖状态对其的影响。 致瘤能力（目标 1）。我们还将描述不同增殖状态的机制 建立并维持。特别是，我们将重点关注 Wnt 通路，以确定个体 Wnt 的作用 驱动不同增殖状态的配体。这些实验的目的是确定靶向的影响 特定增殖状态的 Wnt 信号传导并识别具有强劲生长潜力的其他细胞状态 （目标 2）。肺癌预后较差，但基础科学研究可提高对肺癌的认识 肿瘤异质性可以导致患者治疗方式的重大进步。进一步阐明 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。