Andrew Chan, Ph.D.
Professor
Division of Hematology/Oncology
Dr. Chan comes to the Medical College from Mt. Sinai School of Medicine, in New York City, where he was an associate professor of oncological sciences. He holds a primary appointment in the division of hematology and oncology, Department of Pediatrics. He is also a member of the Medical College Cancer Center, and Children’s Research Institute. His research interests include discovering the molecular basis of cancer, and determining the physiological functions of cancer-causing genes.
Recipient of a Fogarty International Fellowship from the National Institutes of Health, he completed a postdoctoral fellowship in cellular and molecular biology at the National Cancer Institute, in Bethesda, Md., in 1994. He was awarded a five-year Irma T. Hirschl Career Scientist Award in 1996, and received his PhD from the University of London in 1988. He earned his bachelor of science, with honors, from the University of Lancaster, in Lancashire, England, in 1985.
Contact Information
Phone: (414) 456-5659
Email: axchan@mcw.edu
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Research Interests
The long-term research goal is to use mouse models to study different malignant features of human cancer. Focusing on components of the phosphatidylinositol 3-kinase signaling cascade.
1. Roles of PTEN in glioblastoma dispersal
PTEN is a human tumor suppressor gene frequently inactivated in multiple human tumor types. These include endometrial, brain and prostate cancer. PTEN encodes a phosphatidylinositol (3,4,5) triphosphate (PIP3) phosphatase and plays a critical role in regulating the intracellular levels of PIP3. The C-terminal 4-aa (ITKV) of PTEN harbors a consensus-binding motif for Class I PDZ domain proteins. PTEN has been shown to interact with several membrane-localized proteins through this PDZ-binding domain (PDZ-BD) and has been implicated in blocking cell growth and survival.
Human glioblastoma are characterized by their propensity to migrate and invade locally. Over 17% of Grade IV glioblastoma mulitforme (GBM) harbor inactivating mutations in PTEN. These studies also identified a small fraction (~5%) of missense mutations that specifically disrupt the PDZ-BD without affecting the phosphatase activity of PTEN (Figure 1).
Figure 1. Schematic representation of PTEN mutation in human glioblastoma
Current research focuses on identifying novel PTEN interactors that regulate the invasive and migratory properties of GBM. Future characterization of a mouse line lacking PTEN PDZ-BD will shed light on the role of this protein-protein interaction domain in gliomagenesis.
2. Roles of Ras-related G-proteins in neurogenesis and tumor angiogenesis
Members of the Ras subfamily of small GTP-binding proteins play critical roles in a wide spectrum of biological processes. With over twelve evolutionarily conserved members, individuals G-proteins are predicted to propagate unique upstream signals in a tissue specific manner. Our laboratory has identified several members of this gene family including R-Ras, TC21/R-Ras2 and M-Ras/R-Ras3, to possess transforming potential. Examining their expression has revealed a highly restricted pattern of tissue-specific distribution. While R-Ras is highly expressed in lung endothelial cells, TC21/R-Ras2 expression is mainly confined to skeletal muscle, and M-Ras/R-Ras3 is predominantly expressed in astrocytes of the central nervous system (Figure 2).
Figure 2. Expression of Ras-related GTPases in different tissues.
These findings implicate specialized roles for these GTPases in propagating novel signaling events in their respective tissues. Future goals will focus on characterizing knockout mouse strains of these GTPases in order to delineate their physiological functions.
Selected publications
1. Chan, A.M., King, H.W.S., Tempest, P.R., Deakin, E.A., Cooper, C.S. & Brookes, P. (1987) Primary structure of the met protein tyrosine kinase domain. Oncogene 1: 229-233.
2. Rubin, J.S., Chan, A.M., Bottaro, D.P., Burgess, W.H., Taylor, W.G., Cech, A.C., Hirschfield, D.W., Wong. J., Miki. T., Finch, P.W. & Aaronson, S.A. (1991) A broad spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc. Natl. Acad. Sci. U.S.A. 88: 415-419.
3. Bottaro, D.P., Rubin, J.S., Falletto, D.L., Chan, A.M., Kmiecik, T.E., Vande Woude, G.F. & Aaronson, S.A. (1991) Identification of the HGF receptor as the c-met protooncogene product. Science 251: 802-804.
4. Chan, A.M., Rubin, J.S., Bottaro, D.P., Hirschfield, D.W., Chedid, M. & Aaronson, S.A.. (1991) Identification of a competitive HGF Antagonist Encoded by an Alternative Transcript. Science 254: 1382-1385.
5. Miki, T., Bottaro, D.P., Fleming, T.P., Smith, C.L., Burgess, W.H., Chan, A.M. & Aaronson, S.A. (1992) Determination of ligand-binding specificity by alternative splicing: Two distinct growth factor receptors encoded by a single gene. Proc. Natl. Acad. Sci. U.S.A. 89: 246-250.
6. Ishibashi, T., Bottaro, D.P., Chan, A.M., Miki, T. & Aaronson, S.A. (1993) Expression Cloning of a Novel Human Dual Specificity Phosphatase. Proc. Natl. Acad. Sci. U.S.A. 89: 12170-12174.
7. Chan, A.M., Fleming, T.P., McGovern, E.S., Chedid, M., Miki, T. & Aaronson, S.A. (1993) Expression cDNA cloning of a transforming gene encoding the wild-type Galpha12 gene product. Mol. Cell. Biol. 13: 762-768.
8. Chan, A.M., Chedid, M., McGovern, E.S., Popescu, N.C., Miki, T. & Aaronson, S.A. (1993) Expression cDNA cloning of a serine kinase transforming gene. Oncogene 8: 1329-1333.
9. Chan, A.M., McGovern, E.S., Catalano, G., Fleming, T.P. & Miki, T. (1994) Expression cDNA cloning of a novel oncogene with sequence similarity to regulators of small GTP-binding proteins. Oncogene 9: 1057-1063.
10. Kruh, G.D., Chan, A.M., Myers, K., Gaughan, K., Miki, T. & Aaronson, S.A. (1994) Expression cDNA library transfer establishes mrp as a multidrug resistance gene. Cancer Research 54: 1649-1652.
11. Chan, A.M., Miki, T., Meyers, K.A., & Aaronson, S.A. (1994) A new human oncogene of the ras superfamily unmasked by expression cDNA cloning. Proc. Natl. Acad. Sci. U.S.A. 91: 7558-7562.
12. Clark, J., Rocques, P.J., Crew, A.J., Gill, S., Shipley, J., Chan, A.M., Gusterson, B.A. & Cooper, C.S. (1994) Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nature Genetics 7: 502-508.
13. Saez, R., Chan, A.M., Miki, T. & Aaronson, S.A. (1994) Oncogenic activation of human R-ras by point mutations analogous to those of prototype H-ras oncogenes. Oncogene 9: 2977-2982.
14. Huang, Y., Saez, R., Chao, L., Santos, E., Aaronson, S. A. & Chan, A. M. (1995) A Novel Insertional Mutation in the TC21 Gene Activates its Transforming Activity in a Human Leiomyosarcoma Cell Line. Oncogene 11: 1255-1260.
15. Chan, A.M., Takai, S., Yamada, K. & Miki, T. (1996) Isolation of a Novel Oncogene, NET, from neuroepithelioma cells by expression cDNA cloning. Oncogene 12: 1259-1266.
16. Zhang, Y.H., Saez, R., Leal, M. & Chan, A.M. (1996) Synergism between two signaling pathways: Cooperative transformation of NIH/3T3 cells by Ga12 and c-raf-1. Oncogene 12: 2377-2383
17. Tolkacheva, T., Feuer, B., Lorenzi, M.V., Saez, R. & Chan, A.M. (1997) Cooperative transformation of NIH/3T3 cells by Ga12 and Rac1 Oncogene 15: 727-736
18. Kimmelman, A., Tolkacheva, T., Lorenzi, M.V., Osada, M. & Chan, A.M. (1997) Identification and characterization of R-ras3 : a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene 15: 2675 – 2686.
19. Osada, M., Tolkacheva, T., Li, W., Chan, T.O., Tsichlis, P.N., Saez, R., Kimmelman, A.C. & Chan, A.M. (1999) Differential Roles of Akt, Rac, and Ral in R-Ras-Mediated Cellular Transformation, Adhesion, and Survival. Mol. Cell. Biol. 19: 3336-3344.
20. Tolkacheva, T. & Chan, A.M. (2000) Inhibition of H-ras transformation by the PTEN/MMAC1/TEP1 tumor suppressor gene. Oncogene 19: 680-689.
21. Kimmelman, A.C., Osada, M. & Chan, A.M. (2000) R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 19: 2014-2022.
22. Ohba, Y., Mochizuki, N., Yamashita, S., Chan, A.M., Schrader, J.W., Hattori, S., Nagashima, K. & Matsuda, M. (2000) Regulatory Proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J. Biol. Chem. 275: 20020-20026.
23. Tolkacehva, T., Boddapati, M., Sanfiz, A., Tsuchida, K., Kimmelman, A.C. & Chan, A.M. (2001) Regulation of PTEN binding to MAGI-2 by two putative phosphorylation sites at Threonine codon 382 & 383. Cancer Research 61: 4985-4989.
24. Goutham N., Heath, K.E., Reeves, H.L., Li, D., Giono, L.E., Kimmelman, A.C., Glucksman, M.J., Narla, J., Eng, F.J., Chan, A.M., Ferrari, A.C., Martignetti, J.A. & Friedman, S.L. (2001) KLF6, a Candidate Tumor Suppressor Gene Mutated in Prostate Cancer. Science 294: 2563-2566.
25. Chan, T.O., Rodeck, U., Chan, A.M., Kimmelman, A.C., Rittenhouse, S.E., Panayotou, G. & Tsichlis, P.N. (2002) Small GTPases and tyrosine kinases co-regulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell 1: 181-191.
26. Kimmelman, A.C., Nuñez-Rodriguez, N., & Chan, A.M. (2002) R-Ras3/M-Ras induces Differentiation of PC12 cells through a Cell-Type Specific Activation of the Mitogen-Activated Protein Kinase. Mol. Cell. Biol. 22: 5946-5961.
27. Kimmelman, A.C., Qiao, R.F., Narla, G., Sanfiz, A., Bos, P., Banno, A., Nuñez-Rodriguez, N., Lau, N., Li, D., Eng, F.J., Beaven, S., Benzeno, S., Liang, B.C., Guha, A., Martignetti, J.A., Friedman, S.L. and Chan, A.M. (2004) Suppression of Glioblastoma Tumorigenicity by the Kruppel-like Transcription factor, KLF6. Oncogene 23: 5077-5083.
28. Solari, F., Bourbon-Piffaut, A., Masse, I., Payrastre, B., Chan, A.M., & Billaud, M (2005) The human tumor suppressor PTEN regulates longevity and Dauer formation in Caenorhabditis elegans. Oncogene 24: 20-27.
29. Narla, G., Difeo, A., Yao, S., Banno, A., Hod, E., Reeves, H.L., Qiao, R.F., Camacho, O.V., Levine, A., Kirschenbaum, A., Chan, A.M., Friedman, S.L. & Martginetti, J.A. (2005) Targeted Inhibition of the KLF6 Splice Variant, KLF6 SV1, Suppresses Prostate Cancer Cell Growth and Spread. Cancer Research 65: 5761-5768.
30. Rodriguez, N.N., Lee, I.N., Banno, A., Qiao, H.F., Qiao, R.F., Hoang, T., Kimmelman, A.C. & Chan, A.M. (2006) Characterization of R-Ras3/M-Ras null mice reveals a potential role in trophic factor signaling. Mol. Cell. Biol. 26: 7145-7154.
31. Odriozola, L., Singh, G., Hoang, T., & Chan, A.M. (2007) Regulation of PTEN Activity by its Carboxyl-terminal Autoinhibitory domain. J. Biol. Chem. 282: 23306-23315.