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: 10212968
• 负责人: Kenneth Gordon Trieu
• 金额: $ 3.8万
• 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/10212968
• 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.

摘要 基底细胞癌（BCC）是由Hedgehog（Hh）信号通路的组成性激活驱动的， 通常通过PTCH 1的功能缺失突变。我们之前在小鼠身上的研究表明， Ptch 1缺失，显微镜下的BCC样肿瘤优先发生于毛囊干细胞。虽然我们目前 BCC小鼠模型模拟了这种疾病的早期特征和遗传学，我们的初步数据也表明， Ptch 1失活可能不足以完全进展为肉眼可见的肿瘤。最新外显子组测序 研究表明，基底细胞癌是所有癌症中突变负担最高的，因此， 旨在测试人类BCC中观察到的复发性突变是否与Hh信号传导合作来驱动BCC 肿瘤发生事实上，以前的研究表明，NOTCH 1/2和获得性NOTCH 1/2中的功能缺失突变， MYCN中的功能突变通常在BCC中检测到。在这里，我们将研究Notch 1的丢失是否 和/或MYCN的获得与Hh信号传导协作，以驱动成熟的宏观细胞的有效形成。 BCC样肿瘤总的来说，这项建议将确定这些遗传事件是否调节阶段特异性 肿瘤进展，并可能开辟新的治疗靶向策略。