The role of Mtss1 in Hedgehog-mediated intestinal cancer stem cell function

 描述(申请人提供)：根据癌症干细胞假说，癌症的生长是由能够自我更新和分化的长寿命肿瘤细胞驱动的。以哺乳动物肠道为模型系统，我们试图找出调控Lgr5+肿瘤干细胞的新的分子途径。鉴于Akt在癌细胞命运、分化和增殖中的核心作用，我们询问了Tsichlis实验室对Akt磷酸化蛋白质组的最终分析，以确定富含于肠道干细胞和肠道肿瘤中的新型Akt磷酸化底物。在22个候选靶点中，我们选择了Mtss1进行进一步研究。我们通过激活Hedgehog信号，确定Akt特异性的Mtss1磷酸化通过激活Hedgehog信号，在体外细胞和器官模型中驱动肠道癌变和Lgr5+干细胞克隆形成。目前这项提议的目标是研究Mtss1在Hedgehog介导的肿瘤发生和干细胞功能中的作用。在该提案的第一个目标中，我们将研究依赖Mtss1的Hedgehog信号在肠道肿瘤发生中的作用。在该提案的第二个目标中，我们将确定Mtss1在Lgr5+肠癌干细胞功能中的作用。最后，在该提案的第三个目标中，确定Mtss1依赖的Hedgehog信号在Lgr5+肠癌干细胞功能中的作用。我们的建议有望阐明Akt和Hedgehog依赖的癌症干细胞功能机制，为靶向Lgr5+肿瘤干细胞治疗结直肠癌、卵巢癌、胃癌和肝细胞癌提供新的治疗方向。

 DESCRIPTION (provided by applicant): According to the cancer stem cell hypothesis, the growth of cancers is driven by long-lived tumor cells that are capable of self-renewal and differentiation. Using the mammalian intestine as a model system, we sought to identify novel molecular pathways regulating Lgr5+ cancer stem cells. Given the central role of Akt in cancer cell fate, differentiation, and proliferation, we interrogated a definitive analysis of the Akt phosphoproteome by the Tsichlis laboratory to identify novel Akt phosphorylation substrates that are enriched in intestinal stem cells and intestinal tumors. Of 22 candidate targets, we selected Mtss1 for further study. We determined that Akt- specific phosphorylation of Mtss1 drives intestinal carcinogenesis and Lgr5+ stem cell clonogenicity in in vitro cell and organoid models by activating Hedgehog signaling. The goal of the current proposal is to study the role of Mtss1 in Hedgehog-mediated tumorigenesis and stem cell function. In the first aim of the proposal, we will examine the role of Mtss1-dependent Hedgehog signaling in intestinal tumorigenesis. In the second aim of the proposal, we will determine the role of Mtss1 in Lgr5+ intestinal cancer stem cell function. Finally, in the third aim of the proposal, determine the role of Mtss1-dependent Hedgehog signaling in Lgr5+ intestinal cancer stem cell function. Our proposal is expected to elucidate Akt and Hedgehog-dependent mechanisms of cancer stem cell function that will provide new therapeutic directions for targeting Lgr5+ tumor stem cells in colorectal, ovarian, gastric, and hepatocellular cancers.