Vismodegib耐受型髓母细胞癌小鼠模型的构建与应用

Sonic Hedgehog (Shh) is major developmental morphogen in vertebrates, and as such the dysfunction of its signaling is associated with tumorigenesis of many types of cancers. Currently, two Shh pathway-specific antagonists have been approved for clinical treatment of basal cell carcinomas in the skin, but since both drugs target the membrane signaling transducer Smootened, they are not effective against tumors arisen from downstream pathway mutations or non-cannonical pathway activation. We plan to establish medulloblastoma mouse models based on Shh pathway downstream gene Suppressor of fused (Sufu) gene mutations for better understanding how abnormal Shh pathway activation contributes to tumorigenesis, and provide a useful tool for screening non-Smo targeting new generation Shh pathway blockers. Medulloblastoma is the most common childhood brain tumor that originated from cerebellar granule neuron precursors, and is associated with inappropriate Shh pathway activation. Recent genomics research has identified that Sufu mutation as another causal factor in medulloblastoma tumorigenesis. We proprose to 1) establish human Sufu gene mutation-based murine medulloblastoma model; 2) elucidate the role of dual phosphorylation of Sufu on medulloblastoma formation; and 3) investigate the efficacy of using PKA and GSK3 inhibitors for suppressing medulloblastoma cell growth.

髓母细胞瘤是儿童中产生于小脑颗粒性神经元前体细胞的恶性肿瘤，与形态发生因子Sonic Hedgehog (Shh) 通路活性异常增强有密切关系。目前用于临床肿瘤治疗的Shh通路特异性药物都是针对通路上游膜蛋白Smoothened靶点，对由通路下游基因突变以及非经典型通路异常所造成的肿瘤由很大局限性。新近基因组学研究表明Shh通路下游Suppressor of fused (Sufu) 基因突变也是产生髓母细胞癌的重要因素。因此构建基于Sufu基因突变造成的髓母细胞癌小鼠模型将有助于更深入地研究Shh信号转导异常产生肿瘤的机理，并为寻找新一代抗肿瘤的Shh 拮抗剂提供有力工具。在本项目中我们将1）构建基于人类髓母细胞癌Sufu基因突变的小鼠肿瘤模型；2）探讨Sufu双重磷酸化位点对其稳定性的调节在髓母细胞瘤发生中的作用；并且3）探索PKA与GSK3磷酸激酶拮抗剂抑制髓母细胞癌生长的作用。

髓母细胞癌是儿童中产生于小脑颗粒性神经元前体细胞的恶性肿瘤，与形态发生因子Sonic Hedgehog(Shh)通路活性异常增强有密切关系。之前研究发现PKA和GSK3β能够磷酸化Shh通路下游因子Suppressor of fused(Sufu)，增加其稳定性。磷酸化Sufu在髓母细胞癌组织中是高表达的，且之前研究发现Sufu与髓母细胞癌发生有密切关联，因此构建基于Sufu磷酸化变异体造成的髓母细胞癌小鼠模型将有助于更深入地研究Shh信号转导异常产生肿瘤的机理。在本项目中，我们1)构建了Sufu磷酸化变异体及其野生对照小鼠模型；2)研究了Sufu磷酸化变异体小鼠多趾和弱精的表型和机制；3)明确了Sufu在Gli1高表达的人髓母细胞癌组织中是高表达的，且高表达Sufu能够促进小鼠髓母细胞癌的发生；4)发现Sufu能够促进Shh信号通路的转导，进一步证实了Sufu的双重作用机理，为寻找新一代抗肿瘤的Shh拮抗剂提供了新靶点。

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