title: Interfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours.
abstract: Epithelial cancer constitutes a major clinical challenge and molecular mechanisms underlying the process of tumour initiation are not well understood. Here we demonstrate that hair follicle bulge stem cells (SCs) give rise to well-differentiated sebaceous tumours and show that SCs are not only crucial in tumour initiation, but are also involved in tumour plasticity and heterogeneity. Our findings reveal that SC-specific expression of mutant Lef1, which mimics mutations found in human sebaceous tumours, drives sebaceous tumour formation. Mechanistically, we demonstrate that mutant Lef1 abolishes p53 activity in SCs. Intriguingly, mutant Lef1 induces DNA damage and interferes with SC-specific gatekeeper functions normally protecting against accumulations of DNA lesions and cell loss. Thus, normal control of SC proliferation is disrupted by mutant Lef1, thereby allowing uncontrolled propagation of tumour-initiating SCs. Collectively, these findings identify underlying molecular and cellular mechanisms of tumour-initiating events in tissue SCs providing a potential target for future therapeutic strategies.
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Petersson
authors.affiliation: 1] Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany [2] Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Reuter
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Brylka
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kraus
authors.affiliation: 1] Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany [2] Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schettina
authors.affiliation: 1] Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany [2] Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Catherin
authors.initials: C
authors.lastname: Niemann
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D063646:Carcinogenesis; D002273:Carcinogens; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D003433:Crosses, Genetic; D004249:DNA Damage; D018450:Disease Progression; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D012626:Sebaceous Gland Neoplasms / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D002273:Carcinogens; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene