The goal of this project is the elucidation of the role of the Wnt/beta-catenin pathway in sarcomagenesis. In contrast to beta-catenin's role as an oncogene in colorectal cancer, recent observations in our laboratory lead us to hypothesize that b-catenin may function as a tumor suppressor, since its loss of function, as determined by it's failure to accumulate in the nucleus, leads to inhibition of differentiation and maintenance of the tumor phenotype of high grade undifferentiated pleomorphic sarcoma (more commonly called malignant fibrous histiocytoma [HGPS/MFH]), one of the most common sarcoma subtypes. These observations suggest a model of sarcomagenesis in which in which a key event is the lack of nuclear b-catenin accumulation. We plan to test our model and hypothesis in the following specific aims: 1) upregulating beta-catenin in HGPS/MFH cells through transfection of wild-type beta-catenin and assessing for potential reversal of the tumorigenic phenotype; and conversely, downregulating beta-catenin in normal hMSCs (the precursor cells of MFH) and assessing for potential tumorigenesis; 2) characterizing the mechanism of beta-catenin's failure to localize to the nucleus by examining the effect of Wnt/non-canonical signaling on beta-catenin in sarcomas; and 3) identifying beta-catenin target genes relevant to the differentiation/tumorigenesis of sarcoma via ChlP-on-chip promoter factor location analysis using GeneChip ENCODE01 Array complemented by Affymetrix U133a differential gene expression profiling in relation to manipulation of beta-catenin levels in MFH cells. We hope that this work will not only establish a novel function of beta-catenin as a tumor suppressor but also identify its central role in sarcomagenesis thus leading to exploration of specific novel targeted therapies for sarcoma; a family of cancers that has historically proven to be unresponsive to established treatments. ? ? ? ?
