title: Basal Cell Carcinoma in Gorlin's Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?
abstract: Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings suggest that defects in dermo/epidermal interactions could contribute to BCC susceptibility in NBCCS patients.
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Gache
authors.affiliation: CNRS FRE2939, Université de Paris Sud-Institut Gustave Roussy, Villejuif, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Brellier
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rouanet
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Sahar
authors.initials: S
authors.lastname: Al-Qaraghuli
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Goncalves-Maia
authors.affiliation: CNRS FRE2939, Université de Paris Sud-Institut Gustave Roussy, Villejuif, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Burty-Valin
authors.affiliation: UMR 7138, Université Pierre-et-Marie-Curie, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Barnay
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Scarzello
authors.affiliation: CNRS UMR9197, Neuroscience Paris-Saclay Institute, Gif‑sur‑Yvette, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.affiliation: INSERM U916 & Institut Bergonié, Laboratoire de génétique moléculaire, Bordeaux, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sevenet
authors.affiliation: Service de Dermatologie, Université Paris 5-APHP, Paris, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.affiliation: INSERM U1081-CNRS UMR7284 -UNS, Nice, France.|Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Magnaldo
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53