171 COMMD1 Restrains Tumor Promoting Activities of Myeloid Cells in Colon Cancer

Abstract

G A A b st ra ct s primary resistance to imatinib. Amongst c-KIT/PDGFR wild type GIST, the most frequent driver mutation is BRAF-V600E, especially in small intestinal GIST. Thus, a mouse model of mutant Braf GIST might allow for development of more effective therapeutic strategies for these less common forms of GIST. Somatic activating mutations in c-Kit induce ICC hyperplasia and GIST in mouse models. However, whether GIST can arise from other cell types is unknown. In this study, we sought to generate a mouse model for Braf-mutant GIST from intestinal smooth muscle. Methods: Mice with a conditionally active (CA) mutant Braf allele, Braf-lox-stop-lox-V600E (Braf-CA), were crossed to mice carrying the tamoxifeninducible smooth muscle driver (Myh11-CreERT2). Adult mice received a single intraperitoneal injection of tamoxifen, ranging from 2.5-25mg/kg. The stomach, small intestine and colon were evaluated by H&E staining and immunohistochemistry. Results: Three weeks after tamoxifen injection, clusters of dysplastic cells with high nuclear-cytoplasmic ratio were observed in the intestinal muscular layer. The phenotype was most striking at the outer longitudinal layer of the greater curvature of stomach, but was also seen in the small intestinal and colonic muscle layer. The dysplastic cells were spindle-shaped and surrounded ganglion cells. CD34 immunoreactivity decorated, the dysplastic cells, a common finding in human GIST. Some of the clusters of dysplastic cells exhibited c-Kit-positivity and decreased a-SMA staining. c-Kit-positive cell clusters were also positive for anoctamin-1 (Ano1), an additional marker for human c-Kit-positive GIST. Conclusions: By conditionally activating mutant Braf in smooth muscle cells, we have developed a new mouse model for Braf-mutant GIST, as determined by characteristic histological features and markers. These results suggest that smooth muscle, rather than ICC, may be the cell-of-origin for Brafmutant GIST.