Hedgehog (Hh) pathway inhibitors such as vismodegib are highly effective for treating basal cell carcinoma (BCC); however, residual tumor cells frequently persist and regenerate the primary tumor upon drug discontinuation. Here, we show that BCCs are organized into two molecularly and functionally distinct compartments. Whereas interior Hh⁺/Notch⁺ suprabasal cells undergo apoptosis in response to vismodegib, peripheral Hh⁺⁺⁺/Notch^- basal cells survive throughout treatment. Inhibiting Notch specifically promotes tumor persistence without causing drug resistance, while activating Notch is sufficient to regress already established lesions. Altogether, these findings suggest that the three-dimensional architecture of BCCs establishes a natural hierarchy of drug response in the tumor and that this hierarchy can be overcome, for better or worse, by modulating Notch.

中文翻译：

---

肿瘤结构和Notch信号调节基底细胞癌的药物反应。

刺猬（Hh）途径抑制剂，例如vismodegib，对治疗基底细胞癌（BCC）非常有效；但是，残留的肿瘤细胞经常会停药并在停药后再生原发性肿瘤。在这里，我们显示出BCC被组织成两个在分子和功能上截然不同的部分。而内部的Hh ⁺ /缺口⁺基底层细胞经历凋亡响应于vismodegib，外周的Hh ⁺⁺⁺ /缺口^-基底细胞在整个治疗过程中都可以存活。抑制Notch可以特异性地促进肿瘤的持久性而不引起耐药性，而激活Notch则足以消退已经建立的病变。总而言之，这些发现表明，BCC的三维结构在肿瘤中建立了自然的药物反应等级，并且通过调节Notch可以克服这种等级，或多或少。