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

Mtss1在Hedgehog介导的肠癌干细胞功能中的作用

• 批准号: 9754788
• 负责人: Jatin Roper
• 金额: $ 14.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754788
• 关键词: Biological Assay; Biological Models; Cancer Biology; Cell Surface Receptors; Cell physiology; Cells; Colonoscopy; Colorectal Cancer; Dimensions; Engraftment; Erinaceidae; Genetic; Goals; Growth; Human; In Vitro; Intestinal Cancer; Intestinal Neoplasms; Intestines; LGR5 gene; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Molecular; Mus; Organoids; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Play; Population; Primary carcinoma of the liver cells; Regulation; Research; Resistance; Role; Stem cells; Testing; Transplantation; Tumor Stem Cells; adenoma; cancer cell; cancer stem cell; carcinogenesis; colorectal cancer progression; experimental study; improved; in vivo; malignant stomach neoplasm; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; phosphoproteomics; public health relevance; self-renewal; smoothened signaling pathway; stem cell biology; targeted cancer therapy; tumor; tumor initiation; tumorigenesis

 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.

 描述（由适用提供）：根据癌症干细胞假设，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。我们使用哺乳动物肠道作为模型系统，试图确定调节LGR5+癌症干细胞的新型分子途径。鉴于AKT在癌细胞脂肪，分化和增殖中的核心作用，我们通过TSICHLIS实验室对Akt磷酸蛋白酶进行了确定的分析，以鉴定新型的Akt磷酸化底物在肠道干细胞和肠道肿瘤中富集。在22个候选目标中，我们选择了MTSS1进行进一步研究。我们确定MTSS1的Akt-特异性光谱化驱动肠道癌发生和通过激活刺猬信号传导的体外细胞和类器官模型中的LGR5+干细胞结构性。当前建议的目的是研究MTSS1在刺猬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的中，我们将研究MTSS1依赖性刺猬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依赖性刺猬信号在LGR5+肠癌干细胞功能中的作用。我们的建议有望阐明癌症干细胞功能的AKT和刺猬依赖性机制，该机制将为靶向LGR5+肿瘤干细胞的新治疗方向，以结直肠癌，卵巢，胃和肝细胞癌。

项目成果

Myxedema Ascites: An Unusual Presentation of Uncontrolled Hypothyroidism.

粘液性水肿腹水：不受控制的甲状腺功能减退症的异常表现。

• DOI: 10.7759/cureus.2627
• 发表时间: 2018
• 期刊: Cureus
• 作者: Dhingra,Rohit;Rai,Puja;Sieker,Jakob;Roper,Jatin
• 通讯作者: Roper,Jatin

PKM2 is not required for colon cancer initiated by APC loss.

• DOI: 10.1186/s40170-017-0172-1
• 发表时间: 2017
• 期刊: Cancer & metabolism
• 影响因子: 5.9
• 作者: Lau AN;Israelsen WJ;Roper J;Sinnamon MJ;Georgeon L;Dayton TL;Hillis AL;Yilmaz OH;Di Vizio D;Hung KE;Vander Heiden MG
• 通讯作者: Vander Heiden MG