Regulation of Tumor Cell Differentiation by Src Kinases

描述(申请人提供)：缺乏分化是许多癌细胞的特征。由于分化通常与退出细胞周期相协调，因此分化丧失可能是转化表型的原因之一。启动分化途径并导致增殖能力丧失的癌症治疗方法为癌症控制提供了一种新的方法。然而，许多癌症对分化治疗无效，或者对目前使用的药物产生抗药性。缺乏对调控分化的信号通路以及分化和增殖之间存在的反向关系的了解，阻碍了新的分化诱导分子的设计。我们建议通过验证致癌的Src家族激酶异常激活抑制多能细胞分化的信号通路的假设来帮助理解这些途径。了解正常细胞的分化和细胞周期退出对于了解转化细胞中发生的变化至关重要，而小鼠胚胎干细胞为研究这些信号通路提供了一个理想的系统。我们的工作将涉及三个具体目标。首先，我们将检验这样一种假设，即在小鼠ES细胞中，细胞中的Src激酶通常协调退出细胞周期与分化。其次，我们将验证致癌的Src激酶异常激活Stat转录因子和其他抑制ES细胞分化的途径的假设，就像在许多癌细胞中看到的那样。第三，我们将检验这一假设，即在结肠癌细胞中普遍观察到的Src激酶活性升高有助于抑制分化，在某些情况下是通过一种依赖于Stat的机制。除了研究计划外，还提出了一项发展申请人在人类癌症细胞信号领域的专业知识的建议。总之，这些目标的完成将有助于申请者过渡到人类癌细胞生物学基础研究的独立职业生涯。 相关性：诱导细胞分化的药物已经成功地用于治疗数量有限的癌症。这里提出的这项工作旨在确定阻止癌细胞分化的生化途径。了解这些途径有助于设计新的治疗剂，希望将这种类型的治疗扩大到新类型的癌症。

DESCRIPTION (provided by applicant): Lack of differentiation is a hallmark of many cancer cells. Because differentiation is often coordinated with exit from the cell cycle, loss of differentiation may contribute to the transformed phenotype. Cancer therapies that initiate differentiation pathways and result in a loss of proliferative capacity provide a novel approach to cancer control. Many cancers, however, are refractory to differentiation therapy or acquire resistance to currently utilized drugs. A lack of understanding about the signaling pathways that regulate differentiation and the inverse relationship that exists between differentiation and proliferation hinders the design of novel differentiation-inducing molecules. We propose to contribute to the understanding of these pathways by testing the hypothesis that oncogenic Src family kinases aberrantly activate signaling pathways that inhibit differentiation of pluripotent cells. Understanding differentiation and cell cycle exit in normal cells is vital for understanding the changes that occur in transformed cells and mouse embryonic stem (ES) cells provide an ideal system for studying these signaling pathways. Our work will involve three specific aims. First, we will test the hypothesis that cellular Src kinases normally coordinate exit from the cell cycle with differentiation in murine ES cells. Second, we will test the hypothesis that oncogenic Src kinases aberrantly activate Stat transcription factors and other pathways that suppress differentiation in ES cells as seen in many cancer cells. Third, we will test the hypothesis that elevated Src kinase activity commonly observed in colon cancer cells contributes to the inhibition of differentiation, in some cases through a Stat-dependent mechanism. In addition to the research plan, a proposal for the development of the Applicant's expertise in the field of cell signaling in human cancer is presented. Together, completion of these goals will serve to transition the Applicant to an independent career in the basic research of human cancer cell biology. Relevance: Drugs that induce cellular differentiation have been successfully used in the treatment of a limited number of cancers. The work proposed here seeks to identify biochemical pathways that prevent the differentiation of cancer cells. Understanding these pathways can aid in the design of novel therapeutic agents with the hope of expanding this type of therapy to new types of cancer.