Basal cell carcinomas: p53-dependent mechanisms of resistance

描述（由申请人提供）：该项目的目标是更好地了解抑制携带致癌突变的细胞发展为临床显著癌症的内在肿瘤抑制机制。这种抑制对预防基底细胞癌的作用有限，因为基底细胞癌是迄今为止最常见的人类癌症。尽管如此，小鼠模型显示存在非常强的p53依赖性抗bcc效应，并且人类bcc通常携带p53突变。我们(i)将研究突变驱动激活的刺猬信号，BCC癌发生中的关键异常，激活p53的抗癌作用（ii）将阐明p53功能突变丧失（如发生在PTCH1/基底细胞痣综合征患者的人bcc中）和p53功能突变获得（如发生在偶发的人bcc中）的促癌作用之间的差异，（iii）将比较p53依赖性肿瘤抑制对携带hedgehog信号突变的毛囊组织干细胞和携带激活致癌基因的突变等位基因的影响这些途径通常是其他组织癌症的基础，但不是皮肤癌症。该项目的成功实施将有助于阐明为什么这种“异常”癌症如此普遍，为什么不同的遗传背景会影响所发现的p53突变类型，以及为什么特定的组织和细胞会通过特征致癌途径转化。

DESCRIPTION (provided by applicant): The goal of this project is to understand better the mechanisms of intrinsic tumor suppression that inhibit cells carrying oncogenic mutations from developing into clinically significant cancers. This suppression is of limited efficacy in preventing basal cell carcinogenesis, as it is by far the most common human cancer. Nonetheless mouse modeling indicates the presence of very strong p53-dependent anti-BCC effects, and human BCCs routinely carry p53 mutations. We (i) will investigate the connections by which mutation-driven activated hedgehog signaling, the pivotal abnormality in BCC carcinogenesis, activates p53's anti-cancer effects (ii) will elucidate the differences between the pro-carcinogenic effects of p53 loss of function mutations (as occur in human BCCs in PTCH1/basal cell nevus syndrome patients) and p53 gain of function mutations (as occur in human BCCs occurring sporadically) and (iii) will compare the effects of p53-dependent tumor suppression on the hair follicle tissue stem cells carrying mutations of hedgehog signaling vs. carrying mutant alleles activating oncogenic pathways that commonly underlie cancers of other tissues but not of skin. Successful prosecution of this Project will help elucidate why this "outlier" cancer is so common, why different genetic backgrounds can influence the type of p53 mutation found, and why specific tissues and cells are transformed by characteristic oncogenic pathways.