ETV1-positive cells give rise to BRAF(V600E)-mutant gastrointestinal stromal tumors Journal Article


Authors: Ran, L.; Murphy, D.; Sher, J.; Cao, Z.; Wang, S.; Walczak, E.; Guan, Y.; Xie, Y.; Shukla, S.; Zhan, Y.; Antonescu, C. R.; Chen, Y.; Chi, P.
Article Title: ETV1-positive cells give rise to BRAF(V600E)-mutant gastrointestinal stromal tumors
Abstract: Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA–mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. ©2017 AACR.
Journal Title: Cancer Research
Volume: 77
Issue: 14
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2017-07-01
Start Page: 3758
End Page: 3765
Language: English
DOI: 10.1158/0008-5472.can-16-3510
PROVIDER: scopus
PMCID: PMC5513719
PUBMED: 28539323
DOI/URL:
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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Citation Impact
MSK Authors
  1. Yu Chen
    96 Chen
  2. Cristina R Antonescu
    741 Antonescu
  3. Ping Chi
    90 Chi
  4. Leili Ran
    19 Ran
  5. Zhen Cao
    21 Cao
  6. Yuanyuan Xie
    9 Xie
  7. Shipra Shukla
    12 Shukla
  8. Jessica   Sher
    10 Sher
  9. Youxin   Guan
    11 Guan
  10. Yu   Zhan
    5 Zhan
  11. Shangqian   Wang
    17 Wang