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TrkB Signaling in the Genesis of Murine Neuroblastoma

University of Vermont
Rae Nishi, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Update - 6/14:
A paper based on this research was published in Oncogene:

DeWitt J, Ochoa, V, Urschitz J, Elston M, Moisyadi S, and Nishi R. 2014. Constitutively active TrkB confers an aggressive transformed phenotype in a normal neural crest derived cell line. Oncogene 33(8):977-85.

The researchers discovered that expressing an active TrkB receptor in a normal neural crest derived cell line caused the cells to become highly malignant. They grew faster, were highly migratory and invasive, they grew colonies in soft agar (a behavior common to many malignant cells), and they formed tumors that grew quickly. When they profiled the genes that were expressed in the malignant cells and compared them to the normal cells, many genes known to be cancer-related were highly upregulated. In addition, the gene for N-MYC, which is diagnostic for aggressive neuroblastoma was upregulated 30-fold.

Dr. Nishi hopes to continue this project if further funding from NIH can be obtained.

Sympathoadrenal lineage of the neural crest and its etiology is intriguing in that it presents in two forms: one, which spontaneously  regresses; and another, highly aggressive form that has a very high rate of mortality. The influences that promote tumor regression versus progression are unknown, but likely involve altered signaling through neurotrophins, particularly brain derived neurotrophic factor.

Project Goal
We propose that unregulated TrkB activation in these early neuroblasts may be an early event in the genesis of neuroblastoma, with transient activation leading to regressive tumors and prolonged activation initiating a cascade of changes culminating in transformation to aggressive tumors. In collaboration with Dr. William Weiss (UCSF) and Moses Chao (Skirball Institute, NYU) we propose to determine whether sympathetic ganglia from homozygous THMYCN mice, which spontaneously develop neuroblastoma, have altered TrkB signaling.Furthermore, in collaboration with Dr. Felix Eckenstein, we propose to develop a new mouse model of neuroblastoma in which expression of a transforming gene, constitutively active TrkB (TrkB*), together with a vital marker, enhanced green fluorescent protein (EGFP), are induced by tetracycline. The creation of an inducible model of tumorigenesis will allow us to examine in closer detail the temporal timing of gene activation necessary to achieve full transformation, and,in concert with the TH-MYCN mouse, provide a more extensive range of animal models in whichtherapeutic agents may be tested.

Accomplishing these objectives will make it possible for Dr.Nishi’s laboratory to transition from a focus on basic neural development to applying her skills and knowledge towards understanding childhood cancer. These studies will also facilitate the research of the newly formed Neuroblastoma Consortium at the University of Vermont College of Medicine, which includes Drs. G. Sholler, J. Straub, U. Wesley, and M. Bosenberg.