A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gut. GISTs are thought to arise solely from interstitial cells of Cajal (ICC), a KIT-positive population that controls gut motility. Activating gain-of-function mutations in KIT and PDGFRA are the most frequent driver events, and most of these tumors are responsive to the tyrosine kinase inhibitor imatinib. Less common drivers include mutant BRAF^V600E and these tumors are resistant to imatinib. A mouse model of GIST was recently reported using Etv1, the master transcriptional regulator of ICC-intramuscular (IM) and ICC-myenteric (MY), to induce mutant Braf expression. ICC hyperplasia was observed in Etv1^CreERT2;Braf^LSL-V600E/+ mice but loss of Trp53 was required for development of GIST. We identified previously expression of the pan-ErbB negative regulator, LRIG1, in two distinct subclasses of ICC [ICC-deep muscular plexus (DMP) in small intestine and ICC-submucosal plexus (SMP) in colon] and that LRIG1 regulated their development from smooth muscle cell progenitors. Using Lrig1^CreERT2 to induce Braf^V600E, we observed ICC hyperplasia beyond the confines of ICC-DMP and ICC-SMP expression, suggesting smooth muscle cells as the cell-of-origin. To examine this possibility, we selectively activated Braf^V600E in smooth muscle cells. Myh11^CreERT2;Braf^LSL-V600E/+ mice developed not only ICC hyperplasia but also GIST and in the absence of Trp53 disruption. In addition to providing a simpler model for mutant Braf GIST, these results provide conclusive evidence for smooth muscle cells as an alternative cell-of-origin for GIST.