The University of Melbourne
	Department of Surgery
	Royal Melbourne Hospital and Western Hospital

Tumour Biology Laboratory
Unit Head: Dr. Ulrike Novak
e-mail: ulrike@unimelb.edu.au

Staff
Ken Ng- Research Fellow
Nathan Goedde-Research Assistant
Lucy Paradiso- Technical Assistant
Dr. Andrew Morokoff-PhD student

Research Interests: Biology of Brain Tumour Invasion

Gliomas are malignant cerebral tumours, which are invariably fatal. Complete surgical resection of the tumours is impossible as the tumours infiltrate the normal surrounding brain. Therefore some tumour cells will remain after surgery and grow into another tumour. The interactions of the tumour cell with the extracellular matrix and the surrounding normal brain cells regulate the invasive behaviour of the tumour.

Our research centres around two main topics:
1) The expression of EGFR and of ErbB2 in gliomas
2) The expression of ADAM11, ADAM22 and ADAM23 in the brain

1) EGFR and ErbB2 are cell surface receptor tyrosine kinases. They are both overexpressed in gliomas, especially in high-grade gliomas. The EGFR gene is often amplified in these tumours, whereas the ErbB2 gene is not. However, we have found that the ErbB2 gene can be rearranged in a region encoding part of the extracellular domain. We have cloned and sequenced one of these rearrangements and are currently working at characterising a more common rearrangement that we found in about 20% of all high-grade gliomas. We will then study the biological effects of these mutations.

2) ADAM proteins are transmembrane proteins that contain a disintegrin domain and a metalloproteinase domain. The ADAM proteins 11, 22 and 23 are expressed exclusively in the brain, predominantly in neurons, but apparently as well in astrocytes. All three of these proteins lack a Zn-ion binding site and they are therefore not functional metalloproteinases. Their main function could lie in acting as adhesion proteins and in mediating signal transduction events. We have found that they can interact with EGFR and ErbB2 via their extracellular domains and mediate cell binding and migration. Our studies aim at a detailed characterisation of these events in addition at identifying signaling events emanating from the cytoplasmic domain of the ADAM22 protein.

Recent Publications:

45. Novak, U. and A.H. Kaye A.H. (1999). Brain Tumour invasion: Many cooks can spoil the broth. Review. J. Clin. Neurosci. 6, 455-463

46. Novak, U., S.S. Stylli, A.H. Kaye and G. Lepperdinger (1999). Hyaluronidase-2 over-expression accelerates intracerebral but not subcutaneous tumour formation of murine astrocytoma cells. Cancer Research 59, 6246-6250

47. Stylli, S.S., A.H. Kaye and U. Novak. (2000). Induction of CD44 expression in stab wounds of the brain: long term persistence of CD44 expression. J. Clin. Neurosci. 7, 137-140

48. Vadiveloo, P.K., H. Christopolous, U. Novak, P. Hertzog, and J.A. Hamilton (2000). Type I interferons mediate the lipopolysaccharide induction of macrophage cyclin D2. J. Interferon and Cytokine Res. 4, 355-360

49. Novak, U. and A.H. Kaye (2000). Extracellular matrix and the brain: components and function. Review. J. Clin. Neurosci. 7, 280-290

50. Novak, U., F.Walker and A.H.Kaye (2001). Expression of EGFR- family proteins in the brain: role in development, health and disease. J. Clin.Neurosci. 8, 106-111

51. Ernst, M., M. Inglese, P. Waring, I.. Wicks, I.. Campbell, S. Bao, F. J. Clay, W.S. Alexander, I. P. Wicks, D.M. Tarlinton, U. Novak, J. K. Heath and A.R. Dunn. (2001). Defective gp130-mediated Signal Transducer and Activator of Transcription (STAT) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation. J. Exp. Med. 194, 189-204

52. Novak, U. (2001) JAKs (Janus Kinases), in Encyclopedia of Molecular Medicine, published by John Wiley & Sons, Inc. New York , pages 1836-1838, vol 3

53. Enegd, B., J. King, S. Stylli, L. Paradiso, A. Kaye, U. Novak (2002). Overexpression of hyaluronan synthase-2 reduces the tumorigenic potential of glioma cells lacking hyaluronidase activity. Neurosurgery 50, 1311-1318

54. Tsatas, D., V. Kanagasundaram and U. Novak (2002). EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines. J Clin Neurosci., 282-288

55. Novak, U. (2003). ADAM proteins the brain. Review. J.Clin.Neurosci. in press

Research Support:
We acknowledge gratefully the support of our work by the
National Health and Medical Research Council
AntiCancer Council of Victoria,
Friends of the Royal Melbourne Hospital Neuroscience Foundation,
Neurosurgery Foundation (Adelaide), and the
Clive and Vera Ramaciotti Foundation.