Professor of Medicine
Division of Endocrinology, Diabetes and Metabolism
Department of Internal Medicine
Human Cancer Genetics Program
Department of Molecular Virology, Immunology and Medical Genetics
Director, SUCCESS Summer Undergraduate Research Program
Arthur G. James Cancer Hospital and Solove Research Institute
544 Tzagournis Medical Research Facility
420 W 12th Ave
Columbus , OH 43210
Phone: (614) 292-1190
Fax: (614) 247-1622
Dr. Kirschner’s research is aimed at understanding the genetic events leading to the formation of tumors of the endocrine glands, and the relationship of these processes to the differentiation of these tissues. In 2002, Dr. Kirschner identified mutations in the gene PRKAR1A as causing the inherited tumor syndrome Carney Complex. Loss of this gene, which encodes one of the regulatory subunits of the cAMP-dependent protein kinase (Protein Kinase A, or PKA), leads to an increase in PKA activity. Based on this finding, the Kirschner lab focuses on understanding the role of aberrant PKA signaling in the tumorigenic process. We use a combination of mouse modeling and tissue culture work using primary and established cell lines to address these questions. This combined approach allows us to study tumor formation in a living animal and then perform mechanistic studies using cells. Data from one system is used to develop the next set of experiments, with the eventual goal towards the development of new therapeutic agents.
There are currently 3 major focus areas of the lab:
Understanding signaling pathways that cause follicular thyroid cancer:
Thyroid cancer is the most common endocrine cancer, and the cancer whose incidence is rising at the fastest rate. Of the well-differentiated thyroid cancers, follicular thyroid cancer (FTC) accounts for about 15% of cases, and typically behaves more aggressively and carries a poorer prognosis than the more common papillary thyroid cancer (PTC). FTC in humans metastasizes early in the disease course, and we have recently generated a mouse model that mimics the tumor behavior seen in patients. Molecular comparison of human and mouse FTCs suggests that the same pathways are activated, meaning that our model may be a valid means to study human disease. This project is invested in studying the signaling processes that drive tumorigenesis, as well as using this mouse model for the development of new therapeutic strategies.
PKA signaling and its crosstalk with the Neurofibromatosis gene products in Schwann cell tumors.
Schwann cell tumors are observed in 4 inherited disease syndromes: Neurofibromatosis types I and II, Carney Complex, and Familial Schwannomatosis. We have generated a tissue-specific knockout model of Prkar1a which develops schwannomas with high penetrance. Investigation of these tumors has demonstrated mesenchymal-epithelial transition (MET) in the tumors and a post-transcriptional reduction of the NF1 and NF2 proteins. In this project, we aim to understand the crosstalk that causes NF2 downregulation in Prkar1a-KO tumors and how this promotes tumor formation.
The relationship between tumor formation and differentiation in osteoblast cells
Both mice and humans carrying Prkar1a/PRKAR1A mutations develop a specific type of bone tumor known as an osteochondromyxoma. The histology of these tumors includes immature bone and cartilage cells dispersed within a loose myxoid matrix. We have also reported that mice carrying a KO of Prkar1a in the neural crest develop poorly differentiated bone which closely resembles the tumors seen in older Prkar1a+/- animals. Based on these observations, we believe we have an excellent system to probe the relationship between tumor formation and development as it occurs in bone-forming cells. At present, we are using both new KO mouse models and tissue culture cells engineered to lack Prkar1a to study the details of these processes. Eventually, we feel this knowledge may be valuable as a mean to promote the development of bone scaffolds for regenerative medicine.
EDUCATION & TRAINING
Princeton University, Princeton, NJ .1986 A.B. in Chemistry
Albert Einstein College of Medicine, Bronx, NY. 1993 M.D.-Ph.D. in Molecular Pharmacology
1993-96 Internship and Residency in Internal Medicine, University of Minnesota, Minneapolis, MN
1996-99 Clinical Fellowship, Endocrinology and Metabolism, National Institutes of Health, Bethesda, MD
1999-2002 Senior Staff Fellow, Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, NICHD, NIH, Bethesda, MD
1. Kirschner L.S., Carney, J.A., Pack, S., Taymans, S.E., Giatzakis, C.G., Cho, Y.S., Ho-Chung, Y.S., Stratakis C.A. (2000). Mutations of the gene encoding the protein kinase A type I-a regulatory subunit in patients with the Carney complex. Nature Genetics 21:89-92.
2. Kirschner, L.S., Kusewitt, D.F., Matyakhina, L., Towns, W.H., Carney, J.A., Heiner Westphal, H., Stratakis, C.A. (2005) A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues. Cancer Res. 65:4506-14.
3. Nadella, K.S., and Kirschner, L.S. (2005) Disruption of protein kinase A regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res. 2005 65:10307-15.
4. Pavel, E., Nadella, K.S., Towns, W.H., Kirschner, L.S. (2008). Mutation of Prkar1a Causes Osteoblast Neoplasia Driven by Dysregulation of PKA., Mol. Endo. 22:430-40. Epub 2007 Oct 11.
5. Nadella, K.S., Jones, G.N., Trimboli, A., Stratakis, C.A., Leone, G. and Kirschner, L.S. (2008) Targeted deletion of Prkar1a reveals a role for Protein Kinase A in Mesenchymal to Epithelial transition. Cancer Res., 68:2671-7.
6. Jones, G.N., Towns. W.H., Stemmer-Rachamimov, A., Tonks, I.D., Kay, G.F., Yoon, S.O., Kirschner, L.S. (2008) Tissue-specific ablation of Prkar1a causes Schwannomas by suppressing NF Protein Production. Neoplasia, 10:1213-21
7. Jones, G.N., Yin, Z, Powell, K.A., Weinstein, M., LaPerle, K., Kirschner, L.S. (2010) Neural crest –specific ablation of Prkar1a leads to perinatal lethality resulting from malformation of the craniofacial bones. 24:1559-68.
8. Jones GN, Manchanda PK, Pringle DR, Zhang M, Kirschner LS (2010) Mouse models of endocrine tumours. Best Pract Res Clin Endocrinol Metab 24:451-460
9. Pringle DR, Yin Z, Lee AA, Manchanda PK, Yu L, Parlow A, Jarjoura D, Laperle KM, Kirschner LS (2012) Thyroid specific ablation of the Carney Complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer..Endocr Relat Cancer. 19(3):435-46
10. Manchanda, PK, Jones, GN, Lee, AA, Pringle, DR, Zhang, M, Yu, L, La Perle, KMD, Kirschner, LS (2012) Rac1 is required for Prkar1a-mediated Nf2 suppression in Schwann cell tumors, Oncogene in press