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肿瘤细胞驱动的，我们试图使用哺乳动物肠道作为模型系统来鉴定。鉴于 Akt 在癌细胞命运、分化和增殖中的核心作用，我们对 Tsichlis 实验室对 Akt 磷酸化蛋白质组进行了明确的分析，以确定调节 Lgr5+ 癌症干细胞的新分子途径。在 22 个候选靶点中，我们选择了 Mtss1 进行进一步研究，确定 Mtss1 的 Akt 特异性磷酸化可在体外细胞和类器官模型中驱动肠道癌发生和 Lgr5+ 干细胞克隆形成。通过激活 Hedgehog 信号传导 当前提案的目标是研究 Mtss1 在 Hedgehog 介导的肿瘤发生中的作用。在该提案的第一个目标中，我们将研究 Mtss1 依赖性 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 依赖性 Hedgehog 信号在 Lgr5+ 肠癌干细胞功能中的作用。我们的提案预计将阐明 Akt 和癌症干细胞功能的 Hedgehog 依赖性机制将为靶向 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。

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