Regulation of Tumor Cell Differentiation by Src Kinases

描述（由申请人提供）：缺乏分化是许多癌细胞的标志。由于分化通常与细胞周期的退出相协调，因此分化的丧失可能导致表型的转变。启动分化途径并导致增殖能力丧失的癌症治疗为癌症控制提供了一种新的途径。然而，许多癌症对分化治疗是难治的，或者对目前使用的药物产生耐药性。缺乏对调控分化的信号通路和分化与增殖之间存在的反比关系的理解阻碍了新型诱导分化分子的设计。我们建议通过测试致癌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促进对这些途径的理解。了解正常细胞的分化和细胞周期退出对于理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理想的系统。我们的工作将涉及三个具体目标。首先，我们将验证细胞Src激酶通常在小鼠胚胎干细胞分化过程中协调细胞周期退出的假设。其次，我们将验证致癌Src激酶异常激活Stat转录因子和其他抑制胚胎干细胞分化的途径的假设，正如在许多癌细胞中看到的那样。第三，我们将验证在结肠癌细胞中常见的Src激酶活性升高有助于抑制分化的假设，在某些情况下通过stat依赖机制。除了研究计划外，还提出了申请人在人类癌症细胞信号领域发展专业知识的建议。总之，完成这些目标将有助于申请人过渡到人类癌细胞生物学基础研究的独立职业生涯。

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.