ZFIN ID: ZDB-LAB-040510-1
Joanne Chan Lab
PI/Director: Chan, Joanne
Contact Person: Chan, Joanne
Address: Program in Vascular Biology, Children's Hospital, New Research Building, 12th floor, Room 12.217 300 Longwood Avenue Boston, MA 02115-5737 USA
Country: United States
Phone: 617-919-2379
Fax: 617-730-0231
Line Designation: chb

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We are interested in dissecting the molecular mechanisms governing blood vessel formation as it relates to tumor angiogenesis during cancer progression. Our lab uses the zebrafish as a model system to examine blood vessel formation. We are currently using a chemical genetic approach in combination with a mutagenesis screen to identify angiogenic mutants. Positional cloning of these mutants might reveal critical genes as novel targets for anti-angiogenic therapy.

Tumor growth is limited by its blood supply; thus, targeting blood vessels is a rational strategy for cancer treatment. During the formation of tumor vessels, many embryonic genes are reactivated. Our research focuses on using the zebrafish as a model system to examine genes that regulate endothelial cell function. The transparency and rapid development of fish embryos make it possible to detect many phenotypic changes. It is especially well suited for vascular biology studies as the transparency makes it easy to score blood flow as an indication of vessel function. As a vertebrate organism, zebrafish genes their encoded proteins are closely related to their human counterparts so that a small molecule kinase inhibitor designed against the human vascular endothelial growth factor (VEGF) receptor, also inhibits the function of the zebrafish receptor. The VEGF receptor is a major regulator of endothelial cell function in mammals and in the zebrafish. Both VEGF and its receptors are important targets for anti-angiogenic therapy. Recent success with the approval of an anti-angiogenic agent for clinical use has confirmed the feasibility of this approach.

In our work, we use a kinase inhibitor to block the function of the zebrafish VEGF receptor. This highly selective vascular blockade facilitated a chemical genetic dissection of angiogenic signaling in an intact vertebrate organism (Chan et al., 2002). We are currently combining this chemical approach with a mutagenesis screen to identify angiogenic mutants. Identification of the genes responsible for these mutations will further our understanding of the molecular determinants of blood vessel formation that could lead to improved cancer therapies.

Arena, Michael Technical Staff Bellavance, Kimberly Technical Staff Bolcome, Robert Technical Staff

Kawasaki, J., Aegerter, S., Fevurly, R.D., Mammoto, A., Mammoto, T., Sahin, M., Mably, J.D., Fishman, S.J., Chan, J. (2014) RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. J. Clin. Invest.. 124(6):2774-84
Jia, D., Hasso, S.M., Chan, J., Filingeri, D., D'Amore, P.A., Rice, L., Pampo, C., Siemann, D.W., Zurakowski, D., Rodig, S.J., and Moses, M.A. (2013) Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo. Blood. 121(4):707-715
Fevurly, R.D., Hasso, S., Fye, A., Fishman, S.J., and Chan, J. (2012) Novel zebrafish model reveals a critical role for MAPK in lymphangiogenesis. Journal of Pediatric Surgery. 47(1):177-182
Chan, J., and Mably, J.D. (2011) Dissection of cardiovascular development and disease pathways in zebrafish. Progress in molecular biology and translational science. 100:111-153
Hasso, S., and Chan, J. (2011) Chemical approaches to angiogenesis in development and regeneration. Methods in cell biology. 101:181-195
Bolcome, R.E. 3rd, and Chan, J. (2010) Constitutive MEK1 Activation Rescues Anthrax Lethal Toxin-Induced Vascular Effects In Vivo. Infection and Immunity. 78(12):5043-5053
Vasil, M.L., Stonehouse, M.J., Vasil, A.I., Wadsworth, S.J., Goldfine, H., Bolcome, R.E. 3rd, and Chan, J. (2009) A complex extracellular sphingomyelinase of Pseudomonas aeruginosa inhibits angiogenesis by selective cytotoxicity to endothelial cells. PLoS pathogens. 5(5):e1000420
Bolcome, R.E. 3rd, Sullivan, S.E., Zeller, R., Barker, A.P., Collier, R.J., and Chan, J. (2008) Anthrax lethal toxin induces cell death-independent permeability in zebrafish vasculature. Proceedings of the National Academy of Sciences of the United States of America. 105(7):2439-2444
Juris, S.J., Melnyk, R.A., Bolcome, R.E., Chan, J., and Collier, R.J (2007) Crosslinked Forms of the Isolated N-terminal Domain of the Lethal Factor are Potent Inhibitors of Anthrax Toxin. Infection and Immunity. 75(10):5052-5058
Ho, D.M., Chan, J., Bayliss, P., and Whitman, M. (2006) Inhibitor-resistant type I receptors reveal specific requirements for TGF-beta signaling in vivo. Developmental Biology. 295(2):730-742
Bayliss, P.E., Bellavance, K.L., Whitehead, G.G., Abrams, J.M., Aegerter, S., Robbins, H.S., Cowan, D.B., Keating, M.T., O'reilly, T., Wood, J.M., Roberts, T.M., and Chan, J. (2006) Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish. Nature Chemical Biology. 2(5):265-273
Wagle, M., Grunewald, B., Subburaju, S., Barzaghi, C., Le Guyader, S., Chan, J., and Jesuthasan, S. (2004) EphrinB2a in the zebrafish retinotectal system. Journal of neurobiology. 59(1):57-65
Chan, J., and Serluca, F.C. (2004) Chemical approaches to angiogenesis. The Zebrafish: Cellular and Developmental Biology,2nd Ed. Methods Cell Biol.. 76:475-487
Montero, J.-A., Killan, B., Chan, J., Bayliss, P.E., and Heisenberg, C.-P. (2003) Phosphoinositide 3-kinase is required for process outgrowth and cell polarization of gastrulating mesendodermal cells. Current biology : CB. 13(15):1279-1289
Chan, J., Bayliss, P.E., Wood, J.M., and Roberts, T.M. (2002) Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell. 1(3):257-267
Chan, J., Mably, J.D., Serluca, F.C., Chen, J.-N., Goldstein, N.B., Thomas, M.C., Cleary, J.A., Brennan, C., Fishman, M.C., and Roberts, T.M. (2001) Morphogenesis of prechordal plate and notochord requires intact Eph/Ephrin B signaling. Developmental Biology. 234(2):470-482