Journal Article

Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression

Di Rito, Laura, D’Antonio, Eugenia, Rubin, Mark A., Bubendorf, Lukas, Bolis, Marco, Zoni, Eugenio, Jermini, Fernando, Theurillat, Jean-Philippe P., Ceserani, Valentina, Pereira Mestre, Ricardo, Corey, Eva, Mosole, Simone, Moch, Holger, Cavalli, Manuela, Spahn, Martin, Schraml, Peter, Ferrari, Matteo, Vallerga, Arianna, Stoffel, Flavio, Bossi, Daniela, Rinaldi, Andrea, Kruithof-de Julio, Marianna, Elia, Angela Rita, Calcinotto, Arianna, Gillessen, Silke, Impellizzieri, Daniela, Thalmann, George

2021

Overview

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. Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 49 / 49/31 / 49/39 / 49/91 / 631/67/2329 / 631/67/589/466 / 64/60 / Animals / Atlases as Topic / Cell culture / Cell Line, Tumor / Disease Progression / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / G2 Phase Cell Cycle Checkpoints - genetics / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Heterografts / Humanities and Social Sciences / Humans / Macrophages / Macrophages - metabolism / Macrophages - pathology / Male / Mice / multidisciplinary / Mutation / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Perturbation / Polarization / Polycomb group proteins / Polycomb Repressive Complex 2 - genetics / Polycomb Repressive Complex 2 - metabolism / Principal Component Analysis / Prostate - metabolism / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Science / Science (multidisciplinary) / Signal Transduction / Single-Cell Analysis / Trajectory analysis / Transcription / Transcriptome / Transcriptomes / Transcriptomics / Tumors / Xenografts / Xenotransplantation