Investigation of heterogeneity in cancer cell proliferation.

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。

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.