Desmoid tumors are proliferations of relatively benign appearing fibroblasts. Despite their histologic bland appearance, a significant subset of these tumors recurs aggressively and requires often debilitating surgery. Currently there are no molecular markers that predict the behavior of desmoid tumors. The purpose of the study in the third year is to perform a validation of several candidate markers that could be used to address two clinically relevant questions. First, we will validate markers that could distinguish desmoid tumors that can be followed by “watchful waiting” at the time of their initial biopsy from tumors that require aggressive surgical therapy. Second, we will validate overexpression of selected markers in scars as compared with recurrent desmoid tumors to identify markers that could be used in surgical pathology practice to discern these two entities.
This work will build on an the gene expression dataset generated in our laboratory and will benefit from the experience that we have generated in our laboratory for the use of archival formalin-fixed, paraffin-embedded tissue in high throughput studies using next generation sequencing and tissue microarrays. The project greatly benefits from the collaboration with Dr. Kristen Ganjoo at Stanford University Hospital and from the collaboration with Dr. Raffi Avedian, orthopedic surgeon at Stanford. We also plan to continue our collaboration with Drs. Cates and Stricker from Vanderbilt to cross-validate NGS analyses in a range of comparisons.
In the third year of the project we also plan to perform novel functional studies using desmoid cell strains obtained from Dr. Raphael Pollock and Dr. Danielle Braggio from The Ohio State University. It is well characterized that these cell strain cultures are composed of fibroblasts and desmoid cells with mutant β-catenin. It has been shown that fibroblasts exhibit preferential growth in these cultures and eventually outgrowth the desmoid cells. We plan to perform a series of experiments in which we will treat desmoid tumor cell strains with inhibitors of Wnt signaling and γ-secretase to promote growth of desmoid cells and fibroblasts in these cultures, respectively. We anticipate that treatment with Wnt inhibitors will block the endogenous Wnt signaling in fibroblasts and will allow deriving cultures of pure desmoid tumor cells that could be used as an improved model for functional studies, e.g. testing novel drugs in desmoid tumors. This study has been designed and will be performed in collaboration with Dr. Roel Nusse from Stanford University.
LAY VERSION OF ABSTRACT- “Next generation sequencing approach to desmoid tumors.”
