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

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.

MTOR promotes basal cell carcinoma growth through atypical PKC

“…Our bioinformatics analysis and subsequent immunostaining suggests not all tumors possess an MTOR profile, where a subset of tumors showing strong upregulation while others displaying a more modest MTOR signature. This is not surprising as other signaling pathways are known to regulate BCC in conjunction with HH signaling, such as the WNT [42] , NOTCH [43,44] , and Hippo pathways [45] . As such, combination therapy may be an important step going forward to therapeutically treat advanced BCC patients.…”

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

“…Although the proportion of tumors that achieve long-term control with SMO antagonists remains to be established, responses to SMO antagonists may be transient (47)(48)(49), and the combination of HH pathway inhibition with radiation may increase the durability of molecular therapy for BCC patients (although it may also promote additional resistance mechanisms in recalcitrant BCCs) (50,51). BCC cells may survive HH pathway inhibition through chromatin remodeling and enhancer reprogramming, but synergy between Wnt and SMO antagonists, or Notch agonists and SMO antagonists, may be a clinically relevant strategy to prevent relapse (52)(53)(54).…”

LAP2 Proteins Chaperone GLI1 Movement between the Lamina and Chromatin to Regulate Transcription

“…We confirmed cellular entry and the induction of GLI1 hyperacetylation by immunoblot of cultured cells treated with 44LLD compared with a scrambled control (Figure 6H). Treatment of an established murine genetic model of BCC (Eberl et al, 2018) Figures 6J-6L). Treatment of primary human BCCs ex vivo with 44LLD peptide resulted in a 50% reduction of Hh pathway output ( Figure 6M) and GLI1 hyperacetylation (Figure 6N).…”

“…Ptch fl/fl Gli1-CreER T2 Trp53 fl/fl mice All mice were housed under standard conditions, and animal care was in compliance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Stanford University. Ptch fl/fl , Gli1-CreER T2 , Trp53 fl/fl mice were generated and used to generate BCC tumors as described previously (Eberl et al, 2018). For these studies we used only female mice due to the ability to house multiple per cage.…”