Investigation of the role of IQGAP1 in metastasis

Abstract

Metastasis, or the spread of a primary tumor to distal sites in the body, is the major cause of human cancer-related morbidity and mortality. Metastasis requires a complex series of cellular events that remain poorly understood at the molecular level. Recently, advances in microarray technology have allowed cancer biologists to globally survey metastatic progression and define patterns of gene expression that correlate with progression to a metastatic phenotype. By using such a genomic approach, our laboratory identified a subset of genes that regulate the actin cytoskeleton whose enhanced expression correlates with metastasis. This thesis describes the characterization of IQGAP1, a key regulator of the cytoskeleton, as a potentially critical player in metastatic progression. Here I show a strong positive correlation between IQGAP1 expression levels and metastatic progression in both in vivo-selected human metastatic melanoma cells and other human tumors. In addition, I have experimentally analyzed the role of IQGAP1 in metastasis using two different dominant-negative mutants. The results suggest that IQGAP1 may play a functional role in metastatic progression, particularly in the processes of cell migration and invasion. This work lays a scientific framework by which cancer biologists can look at global gene expression analyses and then probe deeper into individual genes to define the molecular mechanisms underlying their roles. In addition, this work contributes to a deeper understanding of the molecular pathogenesis of metastasis, and identifies in IQGAP 1 a potential molecular target for future tumor metastasis therapies.