Gregory M. Shackleford

PIBBS MENTOR

Associate Professor

Pediatrics, Molecular Microbiology & Immunology
Keck School of Medicine
The Saban Research Institute
Childrens Hospital Los Angeles

Research Topics

  • Cancer Genetics

Research Overview

Molecular and Cellular Biology of Cancer

In our laboratory we use techniques of molecular and cell biology to identify cellular genes involved in cancer (proto-oncogenes) and to understand the functions of the protein products of these genes in both tumor cells and normal cells. We are currently concentrating on two families of growth factors: fibroblast growth factors (FGFs) and Wnt factors. Both FGFs and Wnts have oncogenic potential and also have important roles in development.

Cancer is a multistep process resulting from the accumulation of genetic lesions that act together in an additive or synergistic fashion. A major focus of our laboratory is to understand which genes function together in multistep tumorigenesis and how this is accomplished molecularly. To study this process, we have developed a system based on transgenic mice that already harbor one or two active oncogenes but require further mutations for tumor development. We induce these additional mutations by insertional mutagenesis with a retrovirus (mouse mammary tumor virus; MMTV). Because MMTV activates proto-oncogenes by integrating its own genome nearby, the activated genes may be identified and cloned based on their generally close proximity to the newly integrated viral DNA. We have recently identified several fibroblast growth factor (FGF) genes and one FGF receptor as collaborators of the Wnt1 transgene in this manner. We are now extending this system a step further by developing transgenic mice that carry two oncogenes. We will use MMTV insertional mutagenesis of these mice to identify oncogenes that participate at the third stage of multistep tumorigenesis.

In other projects, we are (a) creating new transgenic mice as models for human cancer and analyzing the pathogenic effects of these oncogenic transgenes, (b) examining the potential involvement of matrix metalloproteinases in the Wnt signaling pathway, (c) creating new models for tumorigenesis based on the infection of non-mouse species with MMTV, and (d) studying the positive and negative effects of Wnts and FGFs on apoptosis (programmed cell death).