Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC.Treatment of basal cell carcinoma with Smoothened inhibitors leaves a small population of quiescent cells that can drive relapse but can be eliminated by additional treatment with a Wnt signalling inhibitor.

中文翻译：

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慢循环 LGR5 肿瘤群介导基底细胞癌治疗后复发

基底细胞癌 (BCC) 是人类最常见的癌症，由 Hedgehog 通路的组成型激活引起。几种 Smoothened 抑制剂用于治疗 Hedgehog 介导的恶性肿瘤，包括 BCC 和髓母细胞瘤2。Vismodegib 是一种 Smoothened 抑制剂，可导致大多数 BCC3 患者的 BCC 缩小，但它介导 BCC 消退的机制尚不清楚。在这里，我们使用了两种 BCC4 基因工程小鼠模型来研究抑制 Smoothened 介导肿瘤消退的机制。我们发现vismodegib通过抑制毛囊样命运和促进肿瘤细胞分化来介导BCC消退。然而，一小部分肿瘤细胞持续存在并导致治疗停止后肿瘤复发，模仿人类的情况5。在小鼠和人类 BCC 中，这种持续存在的、缓慢循环的肿瘤群表达 LGR5，并以活跃的 Wnt 信号传导为特征。将 Lgr5 谱系消融或 Wnt 信号通路抑制与 vismodegib 治疗相结合可根除 BCC。我们的研究结果表明，vismodegib 通过促进肿瘤分化诱导肿瘤消退，并证明 Wnt 和 Smoothened 抑制剂之间的协同作用是克服 BCC 肿瘤复发的临床相关策略。 用 Smoothened 抑制剂治疗基底细胞癌会留下少量静止细胞可以导致复发，但可以通过使用 Wnt 信号抑制剂进行额外治疗来消除。缓慢循环的肿瘤群表达 LGR5，并以活跃的 Wnt 信号传导为特征。将 Lgr5 谱系消融或 Wnt 信号通路抑制与 vismodegib 治疗相结合可根除 BCC。我们的研究结果表明，vismodegib 通过促进肿瘤分化诱导肿瘤消退，并证明 Wnt 和 Smoothened 抑制剂之间的协同作用是克服 BCC 肿瘤复发的临床相关策略。 用 Smoothened 抑制剂治疗基底细胞癌会留下少量静止细胞可以导致复发，但可以通过使用 Wnt 信号抑制剂进行额外治疗来消除。缓慢循环的肿瘤群表达 LGR5，并以活跃的 Wnt 信号传导为特征。将 Lgr5 谱系消融或 Wnt 信号通路抑制与 vismodegib 治疗相结合可根除 BCC。我们的研究结果表明，vismodegib 通过促进肿瘤分化诱导肿瘤消退，并证明 Wnt 和 Smoothened 抑制剂之间的协同作用是克服 BCC 肿瘤复发的临床相关策略。 用 Smoothened 抑制剂治疗基底细胞癌会留下少量静止细胞可以导致复发，但可以通过使用 Wnt 信号抑制剂进行额外治疗来消除。