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A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin.
J Pathol. 2020 12; 252(4):441-450.JP

Abstract

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 BRAFV600E 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 Etv1CreERT2 ;BrafLSL-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 Lrig1CreERT2 to induce BrafV600E , 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 BrafV600E in smooth muscle cells. Myh11CreERT2 ;BrafLSL-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. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Authors+Show Affiliations

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA. Department of Clinical Bio-resource Research and Development, Graduate School of Medicine Kyoto University, Kyoto, Japan.Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.Hematology/Medical Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, OR, USA.Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32944951

Citation

Kondo, Jumpei, et al. "A Smooth Muscle-derived, Braf-driven Mouse Model of Gastrointestinal Stromal Tumor (GIST): Evidence for an Alternative GIST Cell-of-origin." The Journal of Pathology, vol. 252, no. 4, 2020, pp. 441-450.
Kondo J, Huh WJ, Franklin JL, et al. A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin. J Pathol. 2020;252(4):441-450.
Kondo, J., Huh, W. J., Franklin, J. L., Heinrich, M. C., Rubin, B. P., & Coffey, R. J. (2020). A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin. The Journal of Pathology, 252(4), 441-450. https://doi.org/10.1002/path.5552
Kondo J, et al. A Smooth Muscle-derived, Braf-driven Mouse Model of Gastrointestinal Stromal Tumor (GIST): Evidence for an Alternative GIST Cell-of-origin. J Pathol. 2020;252(4):441-450. PubMed PMID: 32944951.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A smooth muscle-derived, Braf-driven mouse model of gastrointestinal stromal tumor (GIST): evidence for an alternative GIST cell-of-origin. AU - Kondo,Jumpei, AU - Huh,Won Jae, AU - Franklin,Jeffrey L, AU - Heinrich,Michael C, AU - Rubin,Brian P, AU - Coffey,Robert J, Y1 - 2020/10/15/ PY - 2020/03/05/received PY - 2020/08/27/revised PY - 2020/09/14/accepted PY - 2020/9/19/pubmed PY - 2021/3/16/medline PY - 2020/9/18/entrez KW - animal model KW - gastrointestinal stromal tumor KW - neoplasia KW - smooth muscle KW - stomach SP - 441 EP - 450 JF - The Journal of pathology JO - J Pathol VL - 252 IS - 4 N2 - 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 BRAFV600E 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 Etv1CreERT2 ;BrafLSL-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 Lrig1CreERT2 to induce BrafV600E , 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 BrafV600E in smooth muscle cells. Myh11CreERT2 ;BrafLSL-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. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/32944951/A_smooth_muscle_derived_Braf_driven_mouse_model_of_gastrointestinal_stromal_tumor__GIST_:_evidence_for_an_alternative_GIST_cell_of_origin_ L2 - https://doi.org/10.1002/path.5552 DB - PRIME DP - Unbound Medicine ER -