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

摘要 基底细胞癌(BCC)是由Hedgehog(HH)信号通路的结构性激活驱动的，大多数 通常是通过ptch1功能缺失突变。我们之前在老鼠身上的研究表明，在 Ptch1缺失后，微小的BCC样瘤优先来自毛囊干细胞。虽然我们目前 BCC小鼠模型模拟了该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进展为肉眼肿瘤。最新的外显子组测序 研究表明，基底细胞癌是所有癌症中突变负担最高的，因此，这项建议 寻求测试在人类基底细胞癌中发现的反复突变是否与HH信号协同驱动基底细胞癌 肿瘤发生学。事实上，以前的研究已经表明，NOTCH1/2和NOTCH1/2的功能丧失突变和增益- MYCN的功能突变常见于基底细胞癌。在这里，我们将检查Notch1的丢失 和/或MYCN的增益与HH信号合作，推动全面宏观的有效形成 基底细胞癌样瘤。总体而言，这一提议将决定这些遗传学事件是否调节特定阶段的 肿瘤进展，并可能开辟新的治疗靶向策略。

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.