The Chan Lab is focused on defining the molecular mechanisms governing blood vessel formation as it relates to tumor angiogenesis. The lab uses molecular, chemical genetic and genetic approaches to examine angiogenesis and receptor signaling using the zebrafish as a model system.
The transparency of the zebrafish embryo, its external development and the ability to survive for the first few days of life without a functional circulatory system, make it possible to study genes with critical functions in angiogenesis. As a vertebrate organism, zebrafish genes encoding receptor signaling pathways are highly conserved with their mammalian counterparts (Chan et al., 2001; 2002). This has facilitated our use of a small molecule inhibitor against the vascular endothelial growth factor receptor (VEGFR) to regulate angiogenesis in the fish with the potency and precision approaching a genetic knockout. This chemical genetic approach has allowed us to demonstrate that over-expression of AKT, a downstream component of VEGFR signaling, can rescue an upstream loss of receptor function induced by the inhibitor in an intact embryo (Chan et al., 2002). We also developed a novel screening strategy that combines chemical inhibition with ENU-mutagenesis to identify angiogenic mutants. Each of our mutant lines displays distinctive vascular defects in angiogenic sprouting, vessel remodeling, and/or heart function. Identification of the defective genes will provide insights into the molecular mechanisms of blood vessel formation that might provide novel targets for the development of anti-angiogenic therapy. With the completion of the zebrafish genome on the horizon, these mutants will facilitate our understanding of vertebrate gene function in development and disease.
About Joanne Chan
Joanne Chan was recruited to the Vascular Biology Program by Dr. Folkman in 2003. Dr. Chan has been developing the zebrafish model for cancer and angiogenesis research since her postdoctoral work and instructorship at the Dana-Farber Cancer Institute, in Dr. Thomas Roberts’ lab. While at Dana-Farber, she developed a chemical genetic approach to demonstrate that Akt activation could bypass a functional block in VEGF signaling, and allow blood vessels to form in zebrafish embryos. Since starting her own lab, she has launched a novel chemically sensitized genetic screen for vascular mutations affecting blood vessel guidance, number and function. This work was recognized by a Sidney Kimmel Scholar Award. Dr. Chan’s lab has shown that the VEGF signaling pathway also affects adult angiogenesis during tail fin regeneration. Her work demonstrated enhanced sensitivity to VEGF blockade in genetic lines affecting VEGF signaling, providing a new use of the adult zebrafish. In addition, her lab has defined vascular functions for a number of novel cell surface proteins and receptors using genetics and chemical biology, in the zebrafish model. Currently, her lab has continued to apply genetics and chemical biology to investigate vascular biology questions relevant to angiogenesis and cancer.
Ho DM, Chan J, Bayliss P, Whitman M., Inhibitor-resistant type I receptors reveal specific requirements for TGF-beta signaling in vivo. Dev Biol. 2006 Jul 15;295(2):730-42. Epub 2006 May 8.
Bayliss PE, Bellavance KL, Whitehead GG, Abrams JM, Aegerter S, Robbins HS, Cowan DB, Keating MT, O'Reilly T, Wood JM, Roberts TM, Chan J., Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish. Nat Chem Biol. 2006 May;2(5):265-73. Epub 2006 Mar 26.
Chan J, Serluca FC., Chemical approaches to angiogenesis. Methods Cell Biol. 2004;76:475-87.
Wagle M, Grunewald B, Subburaju S, Barzaghi C, Le Guyader S, Chan J, Jesuthasan S., EphrinB2a in the zebrafish retinotectal system. J Neurobiol. 2004 Apr;59(1):57-65.
Montero JA, Kilian B, Chan J, Bayliss PE, Heisenberg CP. Phosphoinositide 3-kinase is required for process outgrowth and cell polarization of gastrulating mesendodermal cells. Curr Biol. 2003 Aug 5;13(15):1279-89.
Chan J, Bayliss PE, Wood JM, Roberts TM. Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell. 2002 Apr;1(3):257-67.
Chan J, Mably JD, Serluca FC, Chen JN, Goldstein NB, Thomas MC, Cleary JA, Brennan C, Fishman MC, Roberts TM. Related Articles, Links Abstract Morphogenesis of prechordal plate and notochord requires intact Eph/ephrin B signaling. Dev Biol. 2001 Jun 15;234(2):470-82.