Petersson, Monika, Reuter, Karen, Brylka, Heike, Kraus, Andreas, Schettina, Peter and Niemann, Catherin (2015). Interfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours. Nat. Commun., 6. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Petersson, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reuter, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brylka, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraus, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schettina, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niemann, CatherinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-417655
DOI: 10.1038/ncomms6874
Journal or Publication Title: Nat. Commun.
Volume: 6
Date: 2015
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HAIR FOLLICLE BULGE; MOUSE EPIDERMIS; BETA-CATENIN; DNA-DAMAGE; COMET ASSAY; CANCER; DIFFERENTIATION; CARCINOMA; EXPRESSION; MORPHOGENESISMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41765

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