Chromatin Remodeling in Patient-Derived Colorectal Cancer Models.

Autor: Xiang K; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Wang E; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Mantyh J; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Rupprecht G; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Negrete M; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Sanati G; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Hsu C; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Randon P; Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA., Dohlman A; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Kretzschmar K; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Uppsalalaan 8, Utrecht, CT, 3584, The Netherlands.; Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg, 97080, Würzburg, Germany., Bose S; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Giroux N; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Ding S; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Wang L; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Balcazar JP; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Huang Q; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA.; Terasaki Institute, Los Angeles, CA, 90024, USA., Sundaramoorthy P; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Xi R; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., McCall SJ; Department of Pathology, School of Medicine, Duke University, Durham, NC, 27710, USA., Wang Z; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA., Jiang C; Terasaki Institute, Los Angeles, CA, 90024, USA., Kang Y; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Kopetz S; Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Crawford GE; Department of Pediatrics, Division of Medical Genetics, School of Medicine, Duke University, Durham, NC, 27710, USA., Lipkin SM; Department of Medicine and Program in Mendelian Genetics, Weill Cornell Medicine, New York, NY, 10021, USA., Wang XF; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA., Clevers H; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, Uppsalalaan 8, Utrecht, CT, 3584, The Netherlands., Hsu D; Department of Medicine, School of Medicine, Duke University, Durham, NC, 27710, USA., Shen X; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, 27708, USA.; Terasaki Institute, Los Angeles, CA, 90024, USA.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Apr; Vol. 11 (16), pp. e2303379. Date of Electronic Publication: 2024 Feb 21.
DOI: 10.1002/advs.202303379
Abstrakt: Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient-derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, the transcriptomic and chromatin accessibility landscapes of matched colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) are compared. Two major remodeling axes are discovered. The first axis delineates PDMC from PT, and the second axis distinguishes PDX and PDO. PDOX are more similar to PDX than PDO, indicating the growth environment is a driving force for chromatin adaptation. Transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX are identified. Among them, KLF14 and EGR2 footprints are enriched in PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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