Mechanisms of cancer and aging

Mechanisms of cancer and aging

Gene Regulation, Stem Cells and Cancer

Mechanisms of cancer and aging

Group leader
j

Mechanisms of cancer and aging

Group leader
j

2016 Team Leader, IGBMC, Strasbourg, France
2009 Group Leader, Centre for Genomic Regulation (CRG), Barcelona, Spain
2002 Postdoctoral fellow, Cold Spring Harbor Laboratory, USA
2002 Ph.D., Dept. of Physiology, University of Alberta, Edmonton, Canada
1996 M.Med. Sci, Anatomy and Pathology, Queens University Belfast, N. Ireland
1995 B.Sc. (hons), Physiology, University College Galway, Ireland

Important notice

The Keyes lab has moved to the IGBMC, Strasbourg (France).
The new lab webpage is: http://www.igbmc.fr/keyes 

Summary

SENESCENCE AND DEVELOPMENT

Cellular senescence acts as a potent tumor suppressive mechanism, while it can also drive tissue aging and stem cell decline. However, there are aspects to senescence, such as the secretion by senescent cells of growth factors, cytokines and extracellular remodeling factors (the senescence-associated secretory phenotype, or “SASP”) that had been difficult to reconcile and suggested more complex functions for the senescent state. While investigating possible non-classical functions for senescence, we discovered cellular senescence as a normal programmed process during embryonic development. Interestingly, senescence in the embryo is mediated by the expression of p21, exhibits features of the SASP, and instructs local tissue patterning and remodeling. Subsequently, the senescent cells are removed by apoptosis and macrophage-mediated clearance. This unexpected discovery opens up exciting new avenues to unravel the biological importance of the senescence program, its role in embryonic development and patterning, and the correlations with its function in cancer and aging. (Storer et al, Cell, 2013: Storer and Keyes, Comm. Int. Biol, 2014)

STEM CELLS, CANCER AND AGING

Tumor initiation is a complex process involving multiple steps. However, a primary determinant of tumor initiation across most tumor types is age i.e. cancer is a disease of aging. Given that cells expressing markers of hair follicle stem cells (HFSCs) in the skin are a suggested cell of origin during tumor initiation, we wanted to investigate how skin stem cells age, whether they undergo senescence, and if they are altered in their tumor- initiating capacity. To begin to address this, we have performed a detailed study of HFSC aging, including high-throughput RNA-sequencing of aging HFSCs. Surprisingly, we discovered striking alterations in this population of stem cells during the normal aging process. In one study, using a Keratin-15 reporter mouse model that labels a specific sub-population of HFSCs, we found that they increase significantly in number with age, but decrease in function. By analyzing our sequencing data, we identified novel changes in the Jak/Stat signaling pathway in the surrounding tissue that directly impacts stem cell function. In summary, we identified senescence-like changes in aging skin that impact directly on skin stem cell function, and lead to age- related tissue decline. Importantly, this finding has opened up a new area of research investigating the molecular mechanisms of skin stem cell aging. (Doles et al, Genes Dev., 2012: Doles and Keyes, Aging, 2013: Ortells and Keyes, Biochem. Soc. Trans., 2014)

p63, STEM CELLS, SENESCENCE AND CANCER

Another long-running interest in our lab is the mechanisms of tumor initiation and transformation. In particular, we are interested in identifying mutations and factors that can promote tumor development, progression and metastasis, with the aim of identifying novel therapeutic targets. One such study involves the investigation of the p63 transcription factor, and in particular the DNp63a isoform. We recently discovered that this isoform has oncogenic capacity in keratinocytes, and is able to initiate the development of Squamous Cell Carcinoma (SCC) directly by inhibiting the process of oncogene-induced senescence. Surprisingly, in this new model of SCC, which accurately mimics the clinical disease, the transformation from the normal to the transformed state involves multiple steps, including senescence-bypass, clonal expansion, stem-cell deregulation and the required activation of the chromatin remodeling factor, Lsh. In summary, we identified a new cancer causing mutation that provides an ideal model-system to investigate the early stages of tumor initiation and progression. Ongoing questions include the identification of novel p63-targets and stem cell genes that are involved in tumor initiation, and whether similar processes are also found in other tumor types. (Keyes et al, Cell Stem Cell, 2011)