TY - JOUR
T1 - Chromatin Remodeling in Patient-Derived Colorectal Cancer Models
AU - Xiang, Kun
AU - Wang, Ergang
AU - Mantyh, John
AU - Rupprecht, Gabrielle
AU - Negrete, Marcos
AU - Sanati, Golshid
AU - Hsu, Carolyn
AU - Randon, Peggy
AU - Dohlman, Anders
AU - Kretzschmar, Kai
AU - Bose, Shree
AU - Giroux, Nicholas
AU - Ding, Shengli
AU - Wang, Lihua
AU - Balcazar, Jorge Prado
AU - Huang, Qiang
AU - Sundaramoorthy, Pasupathi
AU - Xi, Rui
AU - McCall, Shannon Jones
AU - Wang, Zhaohui
AU - Jiang, Chongming
AU - Kang, Yubin
AU - Kopetz, Scott
AU - Crawford, Gregory E
AU - Lipkin, Steven M
AU - Wang, Xiao-Fan
AU - Clevers, Hans
AU - Hsu, David
AU - Shen, Xiling
N1 - © 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - Colorectal Neoplasms/genetics
KW - Humans
KW - Chromatin Assembly and Disassembly/genetics
KW - Mice
KW - Animals
KW - Organoids/metabolism
KW - Disease Models, Animal
U2 - 10.1002/advs.202303379
DO - 10.1002/advs.202303379
M3 - Article
C2 - 38380561
SN - 2198-3844
VL - 11
SP - e2303379
JO - Advanced Science
JF - Advanced Science
IS - 16
ER -