Catherin Niemann - A 7

Mechanisms of stem cell-specific gatekeeper functions in cancer initiation

The identification of primary genetic hits and the target cell population is of great benefit for an early detection of malignancies and a better prediction of cancer growth. The important finding that stem cells give rise to tumours in a range of tissues is highly relevant for improving current concepts for treatment and for designing preventive therapies. The project aims to decipher stem cell-specific mechanisms driving tumour initiation and to explore targeting disease-initiating events as a promising therapeutic strategy. 

Introduction

Both leukaemia and solid tumours show substantial heterogeneity in their cellular morphology, proliferative index, genetic lesions and therapeutic response. The molecular and cellular mechanisms underlying tumour heterogeneity remain central questions in the field of cancer biology and therapy. It is widely accepted that the pattern of acquired mutations plays a role in determining the tumour phenotype. However, there is strong evidence that tumours of distinct subtypes within an organ are derived from different ‘cells-of-origin’. These cells acquire the first genetic hits that lead to the initiation of cancer. It seems intuitive that identification of these crucial target cell populations may allow discovering tumour-initiating mechanisms and rendering the possibility of earlier detection of malignancies and better prediction of tumour behaviour. Based on significant observations that either stem or progenitor cells act as targets for tumour initiation in a range of solid tumours, including skin cancer, it is crucial to investigate and understand the mechanisms underlying the complex process of stem cell-driven tumour formation and progression. 

Stem cell surveillance mechanisms

Previous work identified hair follicle stem cells as ‘cell-of-origin’ for a variety of different types of epidermal cancer. To address the question why particularly hair follicle stem cells give rise to tumours, molecular and cellular alterations within the stem cell compartment preceding tumour development are under investigation. These experiments revealed that hair follicle stem cells are characterised by faster DNA repair activity when compared to other epidermal cells. In particular, a higher NHEJ (non-homologous end joining) activity through induction of a key protein DNA-PK (DNA-dependent protein kinase) has been identified. Furthermore, our on-going work demonstrates that stem cells feature specific cell death modalities and are less susceptible to undergo apoptosis. 

Together the data suggest that defined mechanisms evolved to maintain stem cells and to safeguard the epidermal tissue.

Having said that, these stem cell-specific mechanisms of error-prone DNA damage repair and protection from undergoing cell death could be harmful and lead to the accumulation of damaged stem cells. Evidently, this has profound implications for cancer development. Currently, the long-term consequences of defective regulation of stem cell safeguard mechanisms for the process of disease formation is investigated.

Stem cell-specific p53 response and cancer

Functional p53 is involved in the regulation of multiple cellular processes, including cell cycle arrest, apoptosis, cellular senescence and DNA damage response. Thus, perturbations in p53 signaling activity are believed to be crucial for the development of most cancers. Interestingly, hair follicle stem cells show accelerated p53 activation in response to tissue damage by irradiation. This essential response mechanism is blocked by oncogenic stress, e.g. expression of a mutant form of the transcription factor Lef1 (Figure 1).

The project investigates causes as well as the underlying mechanisms of an accelerated p53 response detected in hair follicle stem cells. Furthermore, consequences of a defective p53 stem cell response mechanism for the process of epidermal cancer development are currently analysed. This is of particular relevance, given that the tumour suppressor gene TP53 is the most frequently mutated gene in human cancer, including skin cancer, and p53 activity is altered in approximately 50% of human malignancies. 

Cancers lacking p53 mutations often display inactivated wild-type (wt) p53 through modulation of protein interactions (e.g. MDM2/MDM4) resulting in p53 protein degradation. Interestingly, our work investigating oncogenic stress-induced block of p53 activity in hair follicle stem cells revealed that post-translational p53 protein regulation was defective, allowing us to test the possibility restoring p53 function in tumour-initiating stem cells. Generally, there is mounting evidence that restoration of normal p53 function will be of great benefit for cancer therapy. 

Perspectives 

Our recent work shed light on the biological function and control mechanisms of p53 activity in the so far unexplored context of stem cell-driven cancer. In addition, our work will result in novel insights into upstream regulatory pathways leading to a block of p53 function as well as into stem cell-specific mechanisms of p53. Until now it is not sufficiently known how p53 integrates with other oncogenic pathways, including β-catenin/Lef1 signaling. The novel results should be of great importance for a concept of restoration of p53 function in skin cancer as a sound option for therapy. Moreover, better understanding the role of stem cell-specific gatekeeper functions for tumor initiation and cancer stem cell activity in general would be highly beneficial for improving cancer treatment strategies. 

Selected publications

Charcón-Martinez, C.A., Klose, M., Niemann, C., Glauche, I., and Wickström, S.A. (2017). Hair follicle stem cell cultures reveal self-organizing plasticity of stem cells and their progeny. EMBO J. 36, 679-89.

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. 

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.

Petersson, M., and Niemann, C. (2012). Stem cell dynamics and heterogeneity : Implications for epidermal regeneration and skin cancer. Curr Med Chem. 19, 5948-92.


PD Dr. Catherin Niemann

Institute for Biochemistry and CMMC / RG location - CMMC Building

PD Dr. Catherin Niemann

Principal Investigator A 7
Co-Coordinator - IPMM Program
Head - Tissue Embedding and Histology Facility

cnieman1@uni-koeln.de

Work +49 221 478 89511

Fax (Work) +49 221 478 86737

CMMC Research Building
Robert-Koch-Str. 21
50931 Cologne

Publications - Catherin Niemann

Link to PubMed

Group Members

Karen Reuter (PostDoc)
Marcel Drews (doctoral student)
Anna Geueke (doctoral student)
Gökçen Gözüm (doctoral student)
Giada Mantellato (doctoral student)
Jan-Marc Leonhard (technician)
Melanie Nelles (technician)
Peter Schettina (technician)

Figure 1

Defective p53 in epidermal stem cells responding to oncogenic stress (mutant Lef1).
(A) Hair follicle bulge stem cells show accelerated p53 response (green) following UV radiation in wild-type mice, but not in mut. Lef1 mice. (B) Block of p53 protein activation (Phospho-p53) in mut. Lef1 epidermis compared to wild-type epidermis and (C) inhibition of p53 target gene mRNA expression (p21) following UV radiation in stem cells of mut.Lef1 mice.