Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma
Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma
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DOI：
10.1016/j.ccell.2017.12.015
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发表时间：
2018-02-12
期刊：
影响因子：
50.3
通讯作者：
Wong, Sunny Y.
中科院分区：
文献类型：
--
作者：
Eberl, Markus;Mangelberger, Doris;Wong, Sunny Y.
Hedgehog（Hh）通路抑制剂如维莫德吉对治疗基底细胞癌（BCC）非常有效;然而，残留的肿瘤细胞经常持续存在，并在停药后再生原发性肿瘤。在这里，我们表明，BCC被组织成两个分子和功能不同的隔间。尽管内部Hh（+）/Notch（+）基底上细胞响应于维莫德吉而经历凋亡，但外周Hh（+）/Notch（-）基底细胞在整个处理过程中存活。抑制Notch特异性地促进肿瘤持续存在而不引起耐药性，而激活Notch足以使已经建立的病变消退。总而言之，这些发现表明，BCC的三维结构建立了肿瘤中药物反应的自然层次，并且无论好坏，通过调节Notch都可以克服这种层次。
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.