Characterizing Genetic Factors that Modulate Stage-Specific Basal Cell Carcinoma Tumorigenesis

表征调节阶段特异性基底细胞癌肿瘤发生的遗传因素

• 批准号: 10066547
• 负责人: Kenneth Gordon Trieu
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066547
• 关键词: Adult; Affect; Archives; Basal Cell Nevus Syndrome; Basal cell carcinoma; Data; Development; Diagnosis; Erinaceidae; Event; Future; Gene Expression; Genes; Genetic; Genetic Diseases; Goals; Hair follicle structure; Histology; Homeostasis; Human; Lead; MYCN gene; Malignant Neoplasms; Microscopic; Modeling; Molecular; Mus; Mutation; N-Myc Protein; NOTCH1 gene; North America; Other Genetics; Outcome; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Proteins; Recurrence; Sampling; Signal Transduction; Somatic Mutation; Specimen; System; Testing; Tissues; Tumor stage; Up-Regulation; base; driver mutation; exome sequencing; gain of function mutation; loss of function mutation; mouse model; neoplastic cell; new therapeutic target; notch protein; novel therapeutics; overexpression; smoothened signaling pathway; stem cells; tumor; tumor progression; tumorigenesis

ABSTRACT Basal cell carcinoma (BCC) is driven by constitutive activation of the Hedgehog (Hh) signaling pathway, most commonly through loss-of-function mutations in PTCH1. Our previous studies in mice have shown that upon deletion of Ptch1, microscopic BCC-like tumors preferentially arise from hair follicle stem cells. While our current BCC mouse model mimics the early features and genetics of this disease, our preliminary data also suggest that Ptch1 inactivation may not be sufficient for full progression to macroscopic tumors. Recent exome sequencing studies have revealed that BCCs harbor the highest mutational burden of all cancers and therefore, this proposal seeks to test whether recurrent mutations seen in human BCC collaborate with Hh signaling to drive BCC tumorigenesis. Indeed, previous studies have shown that loss-of-function mutations in NOTCH1/2 and gain-of- function mutations in MYCN are commonly detected in BCC. Here, we will examine whether loss of Notch1 and/or gain of MYCN collaborates with Hh signaling to drive the efficient formation of full-blown macroscopic BCC-like tumors. Overall, this proposal will determine whether these genetics events modulate stage-specific tumor progression and may open up novel therapeutic targeting strategies.

抽象的 基底细胞癌（BCC）是由刺猬（HH）信号通路的本构激活驱动的 通常通过PTCH1中的功能丧失突变。我们以前在小鼠的研究表明 PTCH1的缺失，微观BCC样肿瘤优先由毛囊干细胞引起。而我们的当前 BCC小鼠模型模仿了该疾病的早期特征和遗传学，我们的初步数据也表明 PTCH1失活可能不足以完全发展为宏观肿瘤。最近的外显子组测序 研究表明，BCC具有所有癌症的最高突变负担，因此，该提议 试图测试人类BCC中看到的复发突变是否与HH信号合作以驱动BCC 肿瘤发生。实际上，以前的研究表明，Notch1/2的功能丧失突变和 - MYCN中的功能突变通常在BCC中检测到。在这里，我们将检查Notch1是否丢失 和/或MYCN的收益与HH信号合作，以驱动成熟宏观的有效形成 BCC样肿瘤。总体而言，该建议将确定这些遗传事件是否调节特定阶段 肿瘤进展并可能打开新颖的治疗靶向策略。