Abstract
Simple SummaryNevoid basal cell carcinoma syndrome (NBCCS) is a genetic disorder of autosomal dominant inheritance that dramatically predisposes a patient to the formation of basal cell carcinoma (BCC) due to causative mutations in several genes associated with the Hedgehog (Hh) pathway. Somatic mutations in this pathway are also associated with sporadic BCC, the most common form of skin cancer. Hh signalling extends its effect on tumorigenesis by modulating the tumour microenvironment in a paracrine fashion. Consistently, NBCCS fibroblasts could facilitate BCC occurrence. Here, we investigated vismodegib and sonidegib, two molecules currently used to target this pathway in cancer cells, as a therapeutic option against syndromic and BCC-associated fibroblasts.Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the PTCH1 gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/β-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3β axis and consequent increase of β-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.
Highlights
Basal cell carcinoma (BCC) accounts for almost 80% of skin cancers [1,2] and its healthcare workload is principally within dermatology departments
Pharmacological inhibition of the hedgehog pathway (Hh) pathway exerts an anti-tumor effect in several human cell lines, including renal carcinoma [18], oral squamous cell carcinoma [19], breast cancer cells [20] and skin basal cell carcinoma [21]. Another class of patients that benefices from Hh inhibitors are individuals with nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant rare hereditary condition frequently due to germline mutation of patched homolog 1 (PTCH1) gene lacking significant genotype-phenotype correlations [22,23,24]
Consistent with previous evidences demonstrating the absence of hot spot mutation in PTCH1 gene [51,52,53,54], molecular analysis of patients enclosed in this study recorded heterozygotic genetic variation distributed along the entire coding sequence (Table 1)
Summary
Basal cell carcinoma (BCC) accounts for almost 80% of skin cancers [1,2] and its healthcare workload is principally within dermatology departments. Pharmacological inhibition of the Hh pathway exerts an anti-tumor effect in several human cell lines, including renal carcinoma [18], oral squamous cell carcinoma [19], breast cancer cells [20] and skin basal cell carcinoma [21]. Another class of patients that benefices from Hh inhibitors are individuals with nevoid basal cell carcinoma syndrome (NBCCS) ( referred as nevoid BCC syndrome, Gorlin syndrome, or Gorlin Goltz syndrome, OMIM#109400), an autosomal dominant rare hereditary condition frequently due to germline mutation of PTCH1 gene lacking significant genotype-phenotype correlations [22,23,24].
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