aPKC function in Hedgehog signaling and basal cell carcinoma

基底细胞癌（BCC）是世界上最常见的癌症，近一半的美国公民可能在退休前患上这种癌症。BCC是一种侵袭性上皮肿瘤，起源于Hedgehog（Hh）通路中的激活突变，Hh通路是一种重要的发育途径，与约25%的人类癌症死亡有关。尽管Hh信号传导的关键性质，但Hh如何介导癌症中令人印象深刻的增殖缺陷仍然知之甚少。当Hh配体结合并抑制跨膜受体Patched 1时，Hh途径激活开始，允许信号转导子Smoothened（Smo）激活Gli转录因子并放大Hh靶基因的表达。Smo抑制剂最近获得批准用于治疗晚期或转移性BCC，并表现出有效的肿瘤消退。虽然这些抑制剂在初始肿瘤中有效，但侵袭性肿瘤倾向于对药物产生早期耐药性，这说明需要新的治疗靶点。我最近发现，在几乎所有多细胞生物体的发育期间参与干细胞命运选择的至关重要的致癌基因，非典型蛋白激酶C1/λ（aPKC-1/λ）对于BCC中的高、持续的Hh途径活化是必需的。我还发现药理学抑制aPKC抑制小鼠 BCC肿瘤生长以及幼稚和Smo耐药BCC细胞的生长。我研究的目的是 确定允许极性蛋白aPKC-1/λ促进Hh途径活化和幼稚和Smo抗性BCC生长的机制。在K99阶段，我将确定通过aPKC-1/λ的Gli磷酸化如何改变靶基因特异性以促进肿瘤生长，BCC如何调节aPKC-1/λ活性，并测试额外的新型aPKC-1/λ抑制剂用于治疗初治和耐药BCC的治疗潜力。在R 00阶段，我将确定aPKC-1/λ依赖性Gli 1应答基因如何调节肿瘤侵袭，并分析Smo耐药BCC中aPKC-1/λ的功能。这项研究的结果将揭示在BCC期间控制细胞极性和Hh信号传导的保守机制，这将证明在产生用于治疗Hh依赖性癌症的新疗法方面是非常宝贵的。

DESCRIPTION (provided by applicant): 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.