Wnt/β-catenin/Lef1 signalling plays a fundamental role in tissue homeostasis and defects in this crucial signalling cascade often result in tumour formation. We have shown that tissue stem cells displaying abnormal Lef1 activity develop tumours caused by interfering with stem cell-specific gatekeeper functions. This project aims to decipher the molecular mechanism of defective Lef1 signalling activity underlying both, the process of tumour initiation and malignant progression of tumours.
Development of epithelial cancer is not sufficiently understood to successfully treat this heterogeneous disease. It is widely accepted that genetic lesions play a major role in determining the tumour phenotype. In addition, there is mounting evidence demonstrating that cancers of distinct subtypes within an organ derive from different “cells of origin”. These particular cells acquire the first genetic hits that eventually result in cancer growth. Identification of both, the primary genetic hits and the target cell population would be of great benefit for earlier detection of malignancies and a better prediction of cancer growth and progression. Thus, the important finding, that either stem or progenitor cells can act as targets for tumour initiation in a range of solid tumours, is highly relevant for improving concepts for disease targeting and for designing preventive therapies.
The transcription factor Lef1, an important downstream mediator of canonical Wnt signalling, is crucial for development, differentiation and maintenance of many epithelial tissues. We have shown previously that expression of mutant Lef1 in mouse epidermis, thereby mimicking Lef1 mutations found in human skin cancer patients, leads to impaired hair follicle differentiation and spontaneous skin tumours. It will be important to decipher the molecular and cellular mechanism of mutant Lef1 activity to understand its role in the process of cancer initiation and tumour behaviour.
Our work uncovered an important role of hair follicle stem cells in mutant Lef1-driven epidermal tumours. Extensive lineage-tracing studies in tumour whole mounts identified hair follicle bulge stem cells as ‘cells-of-origin’ for mutant Lef1-induced tumours. As a ‘proof of concept’ experiment and to further investigate the specific role of epidermal stem cells for tumour initiation, a transgenic mouse line, expressing mutant Lef1 in hair follicle bulge stem cells was generated. Remarkable, stem cell-driven mutant Lef1 mice developed spontaneous tumours supporting our initial finding that bulge stem cells give rise to epidermal tumours.
To address the question why particular hair follicle bulge stem cells give rise to tumours, molecular and genetic alterations within the stem cell compartment preceding tumour development were investigated in mutant Lef1 mice. Under normal conditions, bulge stem cells are characterised by accelerated DNA repair activity and concomitant attenuation of p53 activation. Intriguingly, mutant Lef1 induced DNA damage (Figure 1) and interfered with these stem cell-specific gatekeeper functions normally protecting against accumulations of DNA lesions and cell loss. Importantly, our work demonstrated that mutant Lef1 abolished p53 activity in stem cells. As a consequence, normal control of stem cell proliferation was disrupted, thereby allowing uncontrolled propagation of tumour-initiating stem cells (Figure 2). Thus, our novel findings point to a crucial function of tissue stem cells for tumour initiation but importantly, our mechanistic results highlights the important role of stem cell-specific surveillance mechanisms for preventing tumour formation.
Our recent data disclose a Lef1-dependent protective mechanism that is specific to (epidermal) stem cells. We will continue investigating how Lef1 regulates DNA damage response and controls p53 activity to better understand how oncogenic pathways affect stem cell-specific surveillance mechanisms. Future research following up on the important finding that cross-regulation between these signalling network is intimately linked to primary events of tumour initiation, could lead to novel therapeutic strategies to successfully interfere with tumour-initiating signals. Given the essential role of Wnt/β-catenin/Lef1 signalling for stem cells of a variety of tissues, the discovery of a mechanistic link between the pathways could be beneficial for malignancies of other organs.
Ali, N.J.A., Dias Gomes, M., Bauer, R., Brodesser, S., Niemann, C., and Iden, S. (2016). Essential role of polarity protein Par3 for epidermal homeostasis through regulation of barrier function, keratinocyte differentiation and stem cell maintenance. J Invest Dermatol. DOI 10.1016/j.jid.2016.07.011
Petersson, M.*, Reuter, K.*, Brylka, H., Schettina, P., Kraus, A., and Niemann, C. (2015). Interfering with stem cell-specific gatekeeper functions controls tumor initiation and malignant progression of skin tumors. Nature Communications 6, 5874. * shared first author.
Frances, D., Sharma, N., Pofahl, R., Maneck, M., Behrendt, K., Reuter, K., Krieg, T., Klein, C.A., Haase, I., and Niemann, C. (2015). A role for Rac1 activity in malignant progression of sebaceous skin tumours. Oncogene 34, 5505-12.
Kloepper, J.E.*, Baris, O.R.*, Reuter, K.*, Kobayashi, K., Weiland, D., Vidali, S., Tobin, D.J., Niemann, C., Wiesner, R.J., and Paus, R. (2015). Mitochondrial function is crucial for hair follicle morphogenesis and epithelial-mesenchymal interactions. J Invest Dermatol. 135, 679-89. * shared first author
Dahlhoff, M., Frances, D., Kloepper, J.E., Paus, R., Schäfer, M., Niemann. C., and Schneider, M.R. (2014). Overexpression of Epigen during embryonic development induces reversible, Epidermal Growth Factor Receptor-dependent sebaceous gland hyperplasia. Mol Cell Biol. 34, 3086-95.
Niemann, C., and Schneider, M.R. (2014). Hair type specific function of canonical wnt activity in adult mouse skin. Exp Dermatol. 23, 881-3.
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Center for Molecular Medicine Cologne - CMMC Research Building
CMMC - PI - assoc. RG 14
IPMM Program - Scientific Coordinator I CMMC Tissue Embedding and Histology & Microscopy - Head
Karen Reuter (PostDoc)
Anna Geueke (doctoral student)
Marcel Drews (doctoral student)
Jan-Marc Leonhard (technician)
Peter Schettina (technician)