FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor
Abstract
The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2018
- Source ID
- 10.1158/2159-8290.cd-17-0468
Entities
People
- Alan Chramiec
- Cristina R Antonescu
- Dan Li
- Devan Murphy
- Deyou Zheng
- Elissa W.P. Wong
- Inna Sirota
- Jenny Q. Zhang
- Jessica Sher
- Katie Yang Li
- Kemal Deniz
- Leili Ran
- Ping Chi
- Richard P. Koche
- Shangqian Wang
- Shipra Shukla
- Youxin Guan
- Yu Chen
- Yuanyuan Xie
- Yuedan Chen
- Zhen Cao
Organizations
- Albert Einstein College of Medicine
- Columbia University
- Cornell University
- Erciyes University
- Gerstner Philanthropies
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- Prostate Cancer Foundation
- United States Department of Defense
- Weill Cornell Medicine