Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression.

Animals Atlases as Topic Cell Line, Tumor Disease Progression Enhancer of Zeste Homolog 2 Protein / genetics G2 Phase Cell Cycle Checkpoints / genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic Heterografts Humans Macrophages / metabolism Male Mice Neoplasm Proteins / genetics Polycomb Repressive Complex 2 / genetics Principal Component Analysis Prostate / metabolism Prostatic Neoplasms / genetics Signal Transduction Single-Cell Analysis Transcriptome

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
02 12 2021

Historique:

received: 04 03 2021

accepted: 20 10 2021

entrez: 3 12 2021

pubmed: 4 12 2021

medline: 5 1 2022

Statut: epublish

Résumé

Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory - reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression.

Identifiants

DOI: 10.1038/s41467-021-26840-5 PMID: 34857732 PMC: PMC8640014

pubmed: 34857732

doi: 10.1038/s41467-021-26840-5

pii: 10.1038/s41467-021-26840-5

pmc: PMC8640014

doi:

Substances chimiques

Neoplasm Proteins 0

EZH2 protein, human EC 2.1.1.43

Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43

Polycomb Repressive Complex 2 EC 2.1.1.43

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

7033

Informations de copyright

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