Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles
| Autor: | Hoi Cheong Siu, April S. Chan, Anthony K W Chan, Jason W. H. Wong, Alice H Y Man, Wai Yin Tsui, Annie S Y Chan, Ho Sang Hui, Bernard C H Lee, Hans Clevers, D Chan, Arthur Kwok Leung Cheung, Siu Lun Ho, Helen H.N. Yan, Sarah S K Yue, Oswens Siu-Hung Lo, Yang Gao, Suet Yi Leung, Wai Lun Law, Siu Tsan Yuen |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2020 |
| Předmět: |
Ubiquitin-Protein Ligases
Adenomatous Polyposis Coli Protein Mutant Bone Morphogenetic Protein 2 Tissue Banks Biology Transcriptome Exome Sequencing Organoid Humans CRISPR Exome Bone Morphogenetic Protein Receptors Type I Smad4 Protein Models Genetic Gene Expression Profiling Receptor-Like Protein Tyrosine Phosphatases Class 2 Gastroenterology Wnt signaling pathway Receptor Protein-Tyrosine Kinases Genetic Profile Phenotype BMPR1A Up-Regulation Organoids Mutation Cancer research CRISPR-Cas Systems Gene Fusion Colorectal Neoplasms Thrombospondins Cell Adhesion Molecules |
| Zdroj: | Gut, 69(12), 2165-2179. BMJ Publishing Group |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | ObjectiveSporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DesignWe established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.ResultsWe observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.ConclusionsThese organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity. |
| Databáze: | OpenAIRE |
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