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FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor

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FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor Published OnlineFirst November 21, 2017; DOI: 10.1158/2159-8290.CD-17-0468 RESEARCH ARTICLE FOXF1 Defi nes the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor Leili Ran 1 , Yuedan Chen 1 , 2 , Jessica Sher 1 , Elissa W.P. Wong 1 , Devan Murphy 1 , Jenny Q. Zhang 1 , Dan Li1 , Kemal Deniz 3 , Inna Sirota 4 , Zhen Cao 1 , 2 , Shangqian Wang 1 , Youxin Guan 1 , Shipra Shukla 1 , Katie Yang Li5 , Alan Chramiec 5 , 6 , Yuanyuan Xie 1 , Deyou Zheng 7 , 8 , 9 , Richard P. Koche 5 , Cristina R. Antonescu 10 , Yu Chen 1 , 2 , 11 , 12 , and Ping Chi 1 , 2 , 11 , 12 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 specifi cation and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specifi c transcriptome through modulation of the local chromatin con- text, 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. SIGNIFICANCE: We uncover that FOXF1 defi nes the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234–51. ©2017 AACR. See related commentary by Lee and Duensing, p. 146. 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Memorial Sloan Kettering Cancer Center, New York, New York. 12 Depart- Cancer Center, New York, New York . 2 Weill Cornell Graduate School of ment of Medicine, Weill Cornell Medical College, New York, New York. 3 Medical Sciences, Cornell University, New York, New York. Department of Note: Supplementary data for this article are available at Cancer Discovery 4 Pathology, Erciyes University, Kayseri, Turkey. Department of Molecular Online (http://cancerdiscovery.aacrjournals.org/). Biology and Genetics, Cornell University, Ithaca, New York. 5 Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, L. Ran and Y. Chen are the co–fi rst authors of this article. New York. 6 Biomedical Engineering, Columbia University, New York, New Corresponding Authors: P. Chi , Memorial Sloan Kettering Cancer Center, York. 7 Department of Genetics, Albert Einstein College of Medicine, Bronx, 1275 York Avenue, New York, NY 10065. Phone: 646-888-3338; Fax: New York. 8 Department of Neurology, Albert Einstein College of Medicine, 646-888-3406; E-mail: [email protected] ; and Y. Chen, [email protected] 9 Bronx, New York. Department of Neuroscience, Albert Einstein College of doi: 10.1158/2159-8290.CD-17-0468 Medicine, Bronx, New York. 10 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 11 Department of Medicine, © 2017 American Association for Cancer Research. 234 | CANCER DISCOVERY FEBRUARY 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 21, 2017; DOI: 10.1158/2159-8290.CD-17-0468 INTRODUCTION and melanoma, where it regulates distinct transcriptional programs (1, 9–11). The enhancer landscape of accessible Gastrointestinal stromal tumor (GIST) is one of the most chromatin defines cellular lineage and the distinct cis- common subtypes of human soft-tissue sarcoma. GIST arises trome and transcriptional output of individual transcrip- from the interstitial cells of Cajal (ICC), a cell lineage that tion factors in different cell types. We thus speculate that requires KIT, the principal signaling regulator, and ETV1, a additional master regulator(s) may function as “pioneer lineage-specific master transcription factor, for lineage speci- factor(s)” that modulate chromatin accessibility and help fication and survival (1–3). Physiologically, normal levels of define and maintain the cistrome of ETV1, analogous to KIT activation by the KIT ligand stabilize the ETV1 protein the pioneer function of FOXA1 to androgen receptor (AR) through active downstream MAPK signaling, and result in in prostate cancer and estrogen receptor-α in breast can- physiologic transcriptional output critical for ICC lineage cer (12–17). Here, we describe the discovery of FOXF1, as specification and development. GIST is characterized by fre- a novel ICC/GIST lineage-specific master regulator that quent activating mutations in KIT. Mutant KIT aberrantly directly regulates KIT, ETV1 expression, and the ICC/GIST activates downstream MAPK signaling, which stabilizes the lineage-specific transcriptome. Moreover, FOXF1 functions ETV1 protein, and stabilized ETV1 in turn enhances mutant as a pioneer factor required to maintain open chromatin and KIT expression. Therefore, mutant KIT and ETV1 form a ETV1 binding at many lineage-specific ETV1-binding sites. positive feedback loop and cooperate in GIST oncogenesis We further demonstrate that FOXF1 functionally is required (4). The lineage-specific expression ofKIT and ETV1 and their for GIST cell growth and survival in vitro and GIST tumor interplay in GIST underline the exquisite therapeutic sen- growth and maintenance in genetically engineered mouse sitivity and clinical success of targeting the lineage depend- models. Overall, our data demonstrate a unique regulatory ence on KIT and ETV1 (5–8). However, how KIT and ETV1 hierarchy of FOXF1 that distinguishes itself from other pio- are regulated and what defines the cellular context in GIST neer factors, e.g., FOXA1, in that beyond chromatin context remain unclear. modulation and active recruitment of ETV1, it also directly In addition to GIST, ETV1 is involved in the tumori- controls the expression of ETV1 and the cooperative signaling genesis of multiple cancer types, including prostate cancer factor KIT. FEBRUARY 2018 CANCER DISCOVERY | 235 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 21, 2017; DOI: 10.1158/2159-8290.CD-17-0468 RESEARCH ARTICLE Ran et al. RESULTS prostate cancer and breast cancer (Fig. 1D). However, FOXA1 expression is low in GIST tumors as well as cell lines (Fig. 1D; FOXF1 Is Nearly Universally and Uniquely Supplementary Fig. S1A and S1B). Expressed in Human GISTs We thus speculate that a different FOX family transcription To identify critical factor(s) that regulate the lineage-spe- factor is involved in the modulation of the ETV1 cistrome cific cellular context for oncogenic transformation, we focused in GIST. We examined the expression of all FOX factors our initial analyses on ETV1, a transcription factor that drives and uncovered that FOXF1 is the highest in both absolute tumorigenesis in two distinct cancer types: prostate cancer expression and significance of differential expression in GIST and GIST (1, 9, 10). We generated genome-wide localization of compared with other cancer types (Fig. 1E; Supplementary ETV1 by chromatin immunoprecipitation sequencing (ChIP- Fig. S1A and Supplementary Table S5). We further examined seq) in two human GIST cell lines (GIST-T1 and GIST48) and RNA-seq profiles of GIST48 and GIST882 cells and observed two prostate cancer cell lines that harbor aberrant expression that FOXF1 was the highest-expressing FOX family member of full-length ETV1 due to translocation of its entire cod- (Supplementary Fig. S1B). We confirmed the presence of ing locus (LNCaP and MDA-PCa2b; refs. 1, 9, 10, 18–20). FOXF1 protein in all three human GIST cell lines, but not in ETV1 cistrome analyses demonstrated that the majority of the negative control melanoma cell lines (OMIM1.3, A375, the ETV1 promoter binding sites (TSS ± 1 kb) were shared and A2058; Fig. 1F). Furthermore, we examined FOXF1 pro- between prostate cancer and GIST, whereas the majority of tein expression in tissue microarrays (TMA) of GIST and nonpromoter (referred as “enhancer” hereafter) binding sites several other sarcoma subtypes from MSK-archived tumor were distinct between the two cancer types (Fig. 1A and B). specimens by immunohistochemistry (IHC). Independent Unsupervised k-means clustering divided enhancer ETV1- review by two sarcoma pathologists confirmed positive FOXF1 binding sites into three distinct clusters of GIST-specific (C1), staining in >98% of all human GIST samples regardless of KIT/ prostate-specific (C2), and shared (C3) sites. This is consistent PDGFRA mutational status, but rarely in other sarcoma sub- with previous observation that enhancer landscape is more types, including myxofibrosarcoma, myxoid liposarcoma, and lineage-specific than promoter (12, 14, 15, 17, 21–24). The synovial sarcoma (Fig. 1G and H). These data demonstrate that observation that ETV1 binds to distinct
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