A smooth muscle-derived,Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternativeGISTcell-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 inKITandPDGFRAare the most frequent driver events, and most of these tumors are responsive to the tyrosine kinase inhibitor imatinib. Less common drivers include mutantBRAF(V600E)and these tumors are resistant to imatinib. A mouse model of GIST was recently reported usingEtv1, the master transcriptional regulator of ICC-intramuscular (IM) and ICC-myenteric (MY), to induce mutantBrafexpression. ICC hyperplasia was observed inEtv1(CreERT2);Braf(LSL-V600E/+)mice but loss ofTrp53was 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. UsingLrig1(CreERT2)to induceBraf(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 activatedBraf(V600E)in smooth muscle cells.Myh11(CreERT2);Braf(LSL-V600E/+)mice developed not only ICC hyperplasia but also GIST and in the absence ofTrp53disruption. In addition to providing a simpler model for mutantBrafGIST, these results provide conclusive evidence for smooth muscle cells as an alternative cell-of-origin for GIST. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.