Faculty, Staff and Student Publications

Publication Date

4-1-2024

Journal

Advanced Science

Abstract

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.

Keywords

Colorectal Neoplasms, Humans, Chromatin Assembly and Disassembly, Mice, Animals, Organoids, Disease Models, Animal, ATAC‐seq, Colorectal Cancer (CRC), Patient‐Derived Models of Cancer (PDMC), Patient‐Derived Organoids (PDO), Patient‐Derived Xenografts (PDX)

DOI

10.1002/advs.202303379

PMID

38380561

PMCID

PMC11040356

PubMedCentral® Posted Date

2-21-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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