Vice President for North America
Herman Yeger, PhD
Department of Paediatric Laboratory Medicine
Division of Pathology
The Hospital for Sick Children
555 University Avenue
Toronto, Ontario M5G 1X8
Tel: 1 416-813-5958
Fax:1 416-813-5974
http://www.sickkids.on.ca
Present Position
Professor of Pathology
Department of Laboratory Medicine & Pathobiology
University of Toronto
Senior Scientist, Research Institute
The Hospital for Sick Children
Societies
Canadian Society for Cell Biology
American Association of Cancer Research
Editorial Board
Journal of Cell Communication and Signaling
Research Themes
Research carried out in my laboratory has followed two areas of investigation relevant to pediatric disease. The first theme has entailed an investigation of the pathogenic mechanisms underlying the etiology and progression of pediatric solid tumors, namely Wilms tumor and neuroblastoma. For these studies we have generated unique cell lines and developed nude mouse and NOD/SCID mouse tumor xenograft models exhibiting primary tumor growth and metastasis. In Wilms tumor, an embryonal tumor of kidney, we have made connections between elevated expression of the HGF/met autocrine growth pathway and metastasis. We have shown association of novH (CCN3) with nephrogenesis and differentiation in Wilms tumors. Taken together, the data suggest that critical growth regulatory events take place at the cell surface that may involve a complex of growth factors, receptors and modulators. Further studies will attempt to unravel the molecular interactions that govern the malignant behavior of tumor cells in different microenvironments and in particular metastasis.
Our studies in neuroblastoma, an embryonal tumor of the peripheral nervous system, have focused on a variety of mechanisms that govern tumor cell growth and survival. We first identified the mevalonate metabolic pathway as a key player in the malignant behavior of neuroblastoma and statins as potential therapeutics that inhibit functions of the pathway. We investigated the therapeutic potential of polyphenolic compounds and their molecular targets. More recently we have identified transcriptional reprogramming via methylation and acetylation as potential means to drive continuing differentiation and inhibit the proliferative drive of these tumors. With teratocarcinomas as a related CNS model we are further exploring the role of CCN proteins in nervous system differentiation and maturation. Here we are developing more complex 3D in vitro systems to mimic in vivo like microenvironments.
The second theme has concentrated on the development and function of the pulmonary neuroendocrine cell (PNEC/NEB) system. This ongoing long-term study is a collaborative effort with Dr. E. Cutz in the department who first identified and characterized this cell system in the lung. The research has evolved from a basic morphological and immunocytochemical characterization to identification of the O2 sensor mechanism and elaboration of ion channel characteristics using electrophysiology. We determined that the hypoxia response of transgenic mice lacking a critical protein component of the O2 sensor, which includes NADPH oxidase, was stunted. From a developmental point of view we are pursuing the identification of PNEC progenitors and related pulmonary stem cells. We have mapped out a complex pattern of PNEC/NEB innervation confirming the neuronal like properties of PNEC/NEB. We have recently demonstrated that these PNEC/NEB cells express functional CFTR while in CFTR deleted mice the hypoxia responsiveness of PNEC/NEB is significantly inhibited. This suggests that CFTR may directly affect neuroendocrine functions and that loss of CFTR may compromise multiple pulmonary functions. In fact, we showed that innervation of PNEC/NEB and amount of smooth muscle were reduced in these knockout mice. The potential involvement of pulmonary PNEC/NEB in the pathobiology of CF disease is clinically relevant.
Recent Publications
Zhang L, Yeger H, Das B, Irwin MS, Baruchel S. Tissue microenvironment modulates CXCR4 expression and tumor metastasis in neuroblastoma. Neoplasia 9: 36-46,2007.
Pan J, Luk C, Kent G, Cutz E, Yeger H. Pulmonary neuroendocrine cells, airway innervation and smooth muscle are altered in Cftr null mice. Am J Respir Cell Mol Biol. 35(3):320-6,2006.
Li W, Kessler P, Yeger H, Alami J, Reeve AE, Heathcott R, Skeen J, Williams BR. A gene expression signature for relapse of primary Wilms tumors. Cancer Res 65:2592-601, 2005.
Torkin R, Lavoie J-F, Kaplan D-R, Yeger H. Induction of caspase-dependent, p53 mediated apoptosis by apigenin in human neuroblastoma. Mol Cancer Ther 4:1-11, 2005.
Kyurkchiev S, Yeger H, Bleau AM, Perbal B. Potential cellular conformations of the CCN3(NOV) protein. Cell Commun Signal 2: 9-15, 2004.
Pan J, Yeger H, Cutz E. Innervation of pulmonary neuroendocrine cells and neuroepithelial bodies in developing rabbit lung. J Histochem Cytochem 52: 379-89, 2004.