title: Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors.
abstract: Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling. To define the role of FGFR3 in human normal and neoplastic epidermis, and to directly test the hypothesis that FGFR3 antagonizes Ras, we engineered human skin grafts in vivo with mutant active FGFR3 or shRNA FGFR3 knockdown. We show that FGFR3 active mutants drive mild hyperproliferation, but are insufficient to support benign or malignant tumorigenesis, either alone, or in combination with G 1-S checkpoint release. This suggests that additional cell-intrinsic or stromal cues are required for formation of benign SKs with FGFR3 mutations. Further, FGFR3 activation does not alter the growth kinetics or differentiation status of engineered human epidermal SCCs driven by Ras, and FGFR3 protein itself is dispensable for Ras-driven SCC. To extend these findings to patients, we examined a uniquely informative human tumor in which SCC developed in continuity with a SK, raising the hypothesis that one of the tumors evolved from the other. However, mutational analysis from each tumor indicates that the overlapping SK and SCC evolved independently and supports our conclusion that FGFR3 activation is insufficient to drive SCC.
authors.affiliation: Department of Dermatology; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA; Cancer Biology Graduate Program; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Duperret
authors.affiliation: Department of Dermatology; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Seung Ja
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Dermatology; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: McNeal
authors.affiliation: Department of Dermatology; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prouty
authors.affiliation: Department of Dermatology; Perelman School of Medicine at the University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Ridky
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D006965:Hyperplasia; D007231:Infant, Newborn; D015603:Keratinocytes / Q000378:metabolism; D017492:Keratosis, Seborrheic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020929:Mitogen-Activated Protein Kinase Kinases; D015689:Oncogene Protein p21(ras)
keywords: extracellular signal-regulated kinase; fibroblast growth factor receptor 3; seborrheic keratosis; skin; squamous cell carcinoma