Role of Integrin-linked kinase in skin homeostasis and carcinogenesis
Final Report Abstract
The aim of this project was to understand the role of the niche in SC homeostasis and cancer, and in particular the role of the niche extracellular matrix (ECM) and cell-matrix interactions in this process. We particularly focused on cell-ECM interaction-mediated signaling through a central adaptor Integrin-linked kinase (ILK) in SC homeostasis and carcinogenesis of the skin. Using the HF as a paradigm for a SC niche we obseved that ILK is required for maintaining the SC niche. Deletion of ILK led to enhanced activation of HFSCs, ultimately resulting in their exhaustion. This was due to altered remodelling of the BM within the SC niche, promoting sustained activation of Wnt and Tgf-β2 pathways and a failure to reestablish quiescence. The enhanced SC activity led to increased replicative stress and DNA damage, which predisposed the ILK-deficient epidermis to skin carcinogenesis. Taken together this data indicates that ILK-mediated remodelling of the niche plays an essential role in SC fate regulation and skin homeostasis. In the second part of the project, we built on the knowledge on the importance of the ECM and the microenvironment to identify a specific combination of niche factors that for the first time allowed expansion and long-term maintenance of HFSCs. Utilizing this system we uncovered self-organizing phenotypic plasticity and dynamic bidirectional interconversion between HFSCs and their progeny, providing a cellular mechanism for homeostatic regulation of a SC niche. In summary, our study delineates how reciprocal interaction between SCs and their niches regulate SC fate and highlights the role of tissue architecture in coordinating cellular behaviours and protecting it from malignant transformation.
Publications
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(2015). Force generation and transmission in keloid fibroblasts: Dissecting the role of mechanosensitive molecules in cell function. Exp Dermatol. 8, 574-575
Schneider D, and Wickström SA
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(2015). Integrinlinked kinase regulates the niche of quiescent epidermal stem cells. Nat Commun. 6:8198
Morgner J, Ghatak S, Jakobi T, Dieterich C, Aumailley M, Wickström SA
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(2016). Hair follicle stem cell cultures reveal self-organizing plasticity of stem cells and their progeny. EMBOJ. 36, 151-164
Chacon-Martinez CA, Klose M, Niemann C, Glauche I, Wickström SA
