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Cancer Cell. 2018 Feb 12;33(2):229-243.e4. doi: 10.1016/j.ccell.2017.12.015. Epub 2018 Jan 27.

Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma.

Author information

1
Departments of Dermatology, and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
2
Departments of Pathology and Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
3
Departments of Dermatology, and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: sunnyw@umich.edu.

Abstract

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.

KEYWORDS:

Hedgehog; Notch; basal cell carcinoma; skin cancer; vismodegib

PMID:
29395868
PMCID:
PMC5811398
DOI:
10.1016/j.ccell.2017.12.015
[Indexed for MEDLINE]
Free PMC Article

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