Queensland Radium Institute

Staff
Funding
Collaborators
Student Projects
Key Recent Publications
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Lab Head: Dr Lyndell Kelly
lyndellK@qimr.edu.au

The Queensland Radium Institute Research laboratory provides a research facility for oncology clinicians. Projects include work on pancreatic cancer, Merkel cell carcinoma and melanocyte stem cells.

Merkel cells
Merkel cells are the touch responders of the skin (the cells which tell you if your skin is being poked or squashed). They derive from the neural crest and when stimulated, secrete compounds to which nerves respond by sending a signal to the brain. Merkel cells are also found at the base of taste buds. Stimulation by salt, acid, etc causes them to secrete substances which excite nerves and result in information being sent to the brain.

[click on image to enlarge]

Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a poor prognosis (30% 3-year survival rates, more like small cell lung cancer than skin cancer) whose incidence is increasing. The cause is chronic long-term exposure to the sun, rather than acute exposure (sunburn) as seen with melanoma. The QRI laboratory has established a tumour bank and a number of cell lines from MCC biopsies, in order to study the biology and aetiology of this little-understood disease.

Our Research
Our investigations into this rare, aggressive skin cancer have shown that the expression of two developmental transcription factors, Brn-3c and HATH 1, can distinguish between cancers which still have a neuroendocrine phenotype and those that have lost expression of these markers. This suggests that these expression patterns may be prognostic in MCC. In addition, we have shown that normal human Merkel cells express Brn-3c and HATH 1. MCC cell lines which retain neuroendocrine phenotype, are slow growing in culture, grow in suspension and are thought to be less aggressive, have been shown to retain Brn-3c and HATH 1 expression. Variant suspension lines which no longer express neuroendocrine markers, retain Brn-3c expression but lack HATH 1. Further, Type IV Variant MCC lines which grow as adherent monolayers, have shorter doubling times, are more radiation resistant and have higher cloning efficiencies in soft agar (all thought to be indicative of aggressive tumours), lack expression of Brn-3c and HATH 1 transcription factors. (see pdf)

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Melanocytes and their precursors, melanoblasts
In collaboration with the laboratory of Dr. Rick Sturm, UQ, we have established a series of melanocyte strains which have all been genotyped for their melanocortin-1 receptor (MC1R) (Sturm, 2001). it has been shown that variants of this protein are responsible for red hair colour and fair skin, and people with this phenotype are more likely to get melanoma (Box et al, 1997, and Sturm, 2002). We have now established a bank of 300 strains of melanocytes to enable us to investigate the relative sensitivities of these strains to ultraviolet light.

In addition, we have recently developed the culture conditions required to grow melanocyte precursors or melanoblasts. The cultures will be useful in analysing the gene expression patterns and protein signal transduction pathways of melanoblasts which may be reactivated during the formation of melanoma tumour cells to form dysplastic melanocytes.

Melanoblasts (left panel) have many dendrites (processes)
while melanocytes (right panel) tend to have only two dendrites

Pancreatic Cancer
We have recently identified a chemical which causes pancreatic cells to undergo cell death by apoptosis. The mechanisms by which this occurs are being examined to determine whether the compound will be useful in the treatment of pancreatic cancer.

Mechanisms of lung cancer
Biopsy material from tumour and normal lung epithelium is being compared by cDNA array technology and 2-D PAGE (see image below) to determine the molecular changes which lead to lung cancer. In the past, normal lung has been used for such studies. The disadvantage of this is that it is not a diverse mix of tissue, whereas epithelium is the tissue of origin for most lung cancer.

2-D protein analysis of cell lysates
Arrows show differences

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Staff

Collaborators

Dr Frank Speleman
Department of Medical Genetics, University Hospital, Ghent, Belgium
Email: franki.speleman@rug.ac.be
Neuroblastoma home page: come.to/neuroblastoma

Dr Rick Sturm
IMB Group Leader, Molecular Genetics of Pigmentation, University of Queensland
Email: R.Sturm@imb.uq.edu.au
http://www.imb.uq.edu.au/sturm.html

Student Projects

Email Helen for more information about collaborations, postgraduate study or research underway in the QRI lab.

Key Publications

Leonard, J.H., Cook, A.L., Van Gele, M., Boyle, G.M., Inglis, K.J., Speleman, F., and Sturm, R.A. Related Articles, Links[Abstract] Proneural and Proneuroendocrine Transcription Factor Expression in Cutaneous Mechanoreceptor (Merkel) Cells and Merkel Cell Carcinoma. Int J Cancer 101:103-110, 2002.[pubmed abstract]

Van Gele, M., Leonard, J.H., Van Roy, N., van Limbergen H., van Belle, S., Cocquvt, V., Salwen, H., De Paepe, A., Speleman, F. Related articles, Links[Abstract] Combined karyotyping, CGH and M-FISH analysis allows detailed characterisation of unidentified chromosomal rearrangements in Merkel cell carcinoma. Int J. Cancer 101:137-145, 2002.[pubmed abstract]

M. Van Gele, J. H. Leonard, N. Van Roy, A. L. Cook , A. De Paepe and F. Speleman Related Articles, Links[Abstract] Identification Of A Pten Nonsense Mutation In Merkel Cell. Int J Cancer 92: 409-413, 2001.[pubmed abstract]

A. L. Cook, P. M. Pollock, J. Welch, M. D. Walsh, R. V. Bowman, K. C. Baumann, N.K. Hayward, J. H. Leonard. Related Articles, Links[Abstract] CDKN2A is not the principle target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin. Int J Cancer 93: 361-367, 2001.[pubmed abstract]

Leonard, J.H., Cook, A.L. Nancarrow, D., Hayward, N., Van Gele, M., Van Roy, N. and Speleman, F. Deletion mapping on the short arm of chromosome 1 in Merkel cell carcinoma Cancer Detection and Prevention 24:620-627, 2000.

M. Van Gele, M Kaghad, J. H. Leonard, N. Van Roy, Naeyaert, J..M.., Geerts, M.L., S. Van Belle, V. Cocquuyt, R. Sciot, C Peeters, A De Paepe, D Caput, and F. Speleman Mutation analysis of p73 and TP53 in Merkel cell carcinoma. Brit J Cancer 82:823-826 2000.

Kelly L, Reid L, Walker NI. Massive acinar cell apoptosis with secondary necrosis, origin of ducts in atrophic lobules and failure to regenerate in cyanohydroxybutene pancreatopathy in rats. Int J Exp Pathol. 80(4):217-26 Aug 1999. [pubmed abstract]

Van Gele, M., Van Roy, N., Naeyaert, J.M., Speleman, F. and Leonard, J.H. Characteristic Pattern of chromosomal gains and losses in Merkel cell carcinoma detected by comparative genomic hybridization. Cancer Res 58:1503-1508, 1998. [pubmed abstract]

Van Gele, M., Van Roy, N., Ronan S.G., Messisen, L., Geerts, M.L., Naeyaert, J.M., Blennow, E., Bar-Am, I., Das Gupta, T. K., Leonard, J.H. and Speleman, F. Molecular analysis of 1p36 breakpoints in two Merkel cell carcinomas. Genes Chromosomes Cancer 23(1):67-71, 1998 [pubmed abstract]

Leonard, J.H., Leonard, P. and Kearsley, J.H., Chromosomes 1, 11 and 13 are frequently involved in karyotypic abnormalities seen in metastatic Merkel cell carcinoma. Cancer Genet. Cytogenet 67: 65-70, 1993. [pubmed abstract]

Thomson, J.A.F., Leonard, J.H., McGregor, K., Sturm, R.A. and Parsons, P.G. A nonconsensus TAATGARAT-like motif identifies a novel DNA binding protein in human Merkel cell carcinoma cell lines. Int. J. Cancer 58: 285-290, 1994. [pubmed abstract]

Leonard, J.H., Dash, P., Holland,.P., Kearsley, J.H. and Bell, J.R. Characterization of four Merkel cell carcinoma adherent cell lines. Int. J. Cancer 60: 100-107, 1995. [pubmed abstract]

Leonard J.H., Ramsay, J.R., Kearsley, J.H. and Birrell, G.W. Radiation sensitivity of Merkel cell carcinoma cell lines. Int. J. Rad. Oncol. Biol. Phys. 32: 1401-1407, 1995. [pubmed abstract]

Leonard, J.H., Bell, J.R. and Kearsley, J.H., Characterization of cell lines established from Merkel cell (small cell) cancer of the skin. Int. J. Cancer 55, 803-810, 1993 [pubmed abstract]

Leonard, J.H., Williams, G., Walters, M.K., Nancarrow, D.J., Rabbitts, P.H. Deletion mapping of the short arm of chromosome 3 in Merkel cell carcinoma. Genes Chromosomes and Cancer 15: 102-107, 1996. [pubmed abstract]

Box, N.F. et al., 1997. Characterization of melanocyte stimulating hormone variant alleles in twins with red hair. Human Molecular Genetics 6: 1891-1897.

Sturm, R.A. et al., 2001. Human pigmentation genes: identification, structure and consequences of polymorphic variation. Gene 277: 49-62.

Sturm, R.A., 2002. Skin colour and skin cancer - MC1R, the genetic link. Melanoma Res 12: 405-416.

A. L. Cook, P. D. Donatien, A G. Smith, M Murphy, M K. Jones, M. Herlyn, D. C. Bennett, J. H Leonard, and R A. Sturm Human Melanoblasts in Culture: Expression of BRN2 and Synergistic Regulation by Fibroblast Growth Factor-2, Stem Cell Factor, and Endothelin-3 Journal of Investigative Dermatology 121, 1150-1159 (2003).

Clinical papers of interest
Poulsen M, Harvey J. Is there a diminishing role for surgery for Merkel cell carcinoma of the skin? a review of current management. ANZ J Surg. 2002 Feb;72(2):142 6. Review.[pubmed abstract]

Poulsen M, Rischin D, Walpole E, Harvey J, Macintosh J, Ainslie J, Hamilton C, Keller J, Tripcony L. Related Articles, Links [Abstract] Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans Tasman Radiation Oncology Group study. Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):156 63. [pubmed abstract]

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