aPKC function in Hedgehog signaling and basal cell carcinoma

项目摘要/摘要：基底细胞癌(BCC)是世界上最常见的癌症，约 有一半的美国公民可能会在退休前患上这种癌症。基底细胞癌是侵袭性上皮性肿瘤， 起源于Hedgehog(HH)途径的激活突变，Hedgehog(HH)途径是一条重要的发育途径， 与大约25%的人类癌症死亡有关。尽管HH的本质是关键的 在信号方面，HH如何介导癌症中令人印象深刻的增殖性缺陷仍然知之甚少。HH 当HH配体结合并抑制跨膜受体Patched1时，通路开始激活，从而 信号转导分子Smo激活Gli转录因子并扩增HH靶基因的表达 基因。SMO抑制剂最近获得批准用于治疗晚期晚期或转移性基底细胞癌和 表现出强大的肿瘤消退。虽然这些抑制物对幼稚肿瘤有效，但侵袭性肿瘤往往 对药物产生早期抗药性，说明需要新的治疗靶点。我最近有过 发现一种至关重要的癌基因，非典型蛋白激酶C_1OTA/λ(APKC-ι/λ)，参与了 干细胞在几乎所有多细胞生物体发育过程中的命运选择对于高度、持续的 膀胱移行细胞癌HH通路的激活。我还证明了对蛋白激酶C的药理抑制可以抑制小鼠 BCC肿瘤的生长以及幼稚和耐Smo的BCC细胞的生长。我的研究目标是 确定允许极性蛋白aPKC-ι/λ促进HH途径激活和 天真和抵制Smo的BCC增长。在K99阶段，我将确定Gli是如何通过 APKC-ι/λ改变靶基因特异性以促进肿瘤生长，BCC如何调节APKC-ι/λ活性，以及 测试新的aPKC-ι/λ抑制剂治疗幼稚和耐药的可能性 密件抄送。在R00阶段，我将确定依赖PKC-ι/λ的Gli1反应基因如何调控肿瘤 侵袭并分析PKC-ι/λ在耐Smo的BCC中的作用。这项研究的结果将揭示保守的 在BCC过程中管理细胞极性和HH信号的机制将被证明是非常宝贵的 治疗HH依赖型癌症的新疗法。

Project Summary/Abstract: Basal cell carcinoma (BCC) is the most prevalent cancer in the world and nearly half of US citizens are likely to develop this cancer before retirement. BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway, an essential developmental pathway that has been implicated in approximately 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates the impressive proliferative defects in cancers remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained approval for treatment of late advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in naïve tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need for new therapeutic targets. I have recently discovered that a critically important oncogene, atypical Protein Kinase C iota/lambda (aPKC-ι/λ), involved in stem cell fate choice during development of nearly all multicellular organisms is essential for high, sustained Hh pathway activation in BCCs. I have also shown pharmacological inhibition of aPKC suppresses murine BCC tumor growth and the growth of naïve and Smo-resistant BCC cells. The goal of my research is to determine the mechanisms that allow the polarity protein aPKC-ι/λ to promote Hh pathway activation and naïve and Smo-resistant BCC growth. During the K99 phase, I will determine how phosphorylation of Gli by aPKC-ι/λ alters target gene specificity to promote tumor growth, how BCC's regulate aPKC-ι/λ activity, and test the therapeutic potential of additional novel aPKC-ι/λ inhibitors for the treatment of naïve and resistant BCC. During the R00 phase, I will determine how aPKC-ι/λ -dependent Gli1 responsive genes regulate tumor invasion and analyze aPKC-ι/λ function in Smo-resistant BCCs. The results of this study will reveal conserved mechanisms that govern cell polarity and Hh signaling during BCC that will prove invaluable in generating novel therapeutics for the treatment of Hh-dependent cancers.