Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma
Volume 33, Issue 2, p229–243.e4, 12 February 2018
- Hedgehog pathway inhibitors are effective against BCC, but tumor cells often persist
- Tumor basal and suprabasal cells differ in gene expression and drug response
- Inhibiting Notch promotes tumor persistence, but not drug resistance, upon treatment
- Latently activating Notch is sufficient to regress already established tumors
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.
Although therapeutics targeting the Hedgehog signaling pathway are highly effective at treating basal cell carcinoma (BCC), cancer cells frequently persist and regenerate the primary tumor once treatment is stopped. Our findings suggest that persistent cancer cells likely originate from the tumor periphery and display low Notch pathway activity. In contrast, cancer cells located at the interior of the tumor mass activate Notch and are efficiently eliminated by drug treatment. These findings suggest that the cellular architecture of BCC, likely determined by contact with the surrounding basement membrane, may influence whether tumor cells persist or are destroyed in response to therapy.