Pathology & Lab Medicine
Area of interest
Recent studies have implicated aberrant activity of chromatin remodeling complexes in the development of human cancer. Mutations in the INI1/SNF5/BAF47 gene, a component of the SWI/SNF chromatin remodeling complex, occur in virtually all malignant rhabdoid tumors (MRTs). Originally identified in yeast, the SWI/SNF complex alters chromatin structure by remodeling nucleosomes through an ATP-dependent process. Loss or expression of the SWI2 ATPase homologs, BRG1 and BRM, by promoter methylation and/or mutations of either or both genes occurs in ~25% of human NSCLC cell lines and ~10% of primary human NSCLCs. Importantly, several groups, including our own, have shown a correlation between loss of expression of BRG1/BRM and poor prognosis in NSCLC patients. Our laboratory focuses on the dissecting the mechanisms by which the loss of function of these SWI/SNF components fuel human tumor development. We are currently characterizing novel targets of SNF5 in human MRT cell culture models and assessing the effects of SNF5 loss on chromatin structure and modifications in their promoter regions. We are also identifying downstream targets of SNF5 associated with MRT development using a combination of high-throughput DNA sequencing approach (ChIP-seq) and gene expression array analyses. Finally, we are determining the role of Snf5 inactivation in neural cell development and malignant rhabdoid tumorigenesis using novel genetically engineered mouse models, neurosphere cultures and a comparison of mouse spinal cord MRTs with human MRTs of the central nervous system. We have also developed a cell culture model where silencing of BRG1 expression by RNAi in a human NSCLC leads to loss of expression of a similar array of gene observed in NSCLC cell lines with a spontaneously arising BRG1 null mutation. We are currently characterizing the promoters of these genes to determine their status in the presence and absence of SWI/SNF complex activity. In a complementary in vivo approach, we have generated a genetically engineered mouse model by crossing LSL-KrasG12D/+ mice with Brg1fl/+ and/or Brm-/- mice to generate LSL-KrasG12D/+;Brg1fl/+ mice and LSL-KrasG12D/+;Brm-/- mice. We have then induced lung tumor development by intra-nasal exposure to adenoviral-CRE. Our initial results show that Brm inactivation does not affect overall survival but does increase angiogenesis in the lung tumors. In contrast, loss of one Brg allele increases overall survival yet increases the frequency of invasive tumors in the mice. We are currently characterizing the tumors from these animals to determine the underlying molecular mechanisms that account for these results.
Awards and Honors
We have shown that reexpression of SNF5 in malignant rhabdoid tumors causes a rapid induction of G1 arrest through increased expression of the p21WAF1/CIP1 gene. In some MRT cell lines, the induction does not appear dependent upon the p53 pathway.