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Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. It is known that the tumor microenvironment (TME) regulates tumorigenesis and metastasis. However, how the malignant progression in RB is determined by the heterogeneity of tumor cells and TME remains uncharacterized...

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Autores principales: Wu, Cheng, Yang, Jiaqi, Xiao, Wei, Jiang, Zehang, Chen, Shuxia, Guo, Dianlei, Zhang, Ping, Liu, Chunqiao, Yang, Huasheng, Xie, Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076657/
https://www.ncbi.nlm.nih.gov/pubmed/35523772
http://dx.doi.org/10.1038/s41419-022-04904-8
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author Wu, Cheng
Yang, Jiaqi
Xiao, Wei
Jiang, Zehang
Chen, Shuxia
Guo, Dianlei
Zhang, Ping
Liu, Chunqiao
Yang, Huasheng
Xie, Zhi
author_facet Wu, Cheng
Yang, Jiaqi
Xiao, Wei
Jiang, Zehang
Chen, Shuxia
Guo, Dianlei
Zhang, Ping
Liu, Chunqiao
Yang, Huasheng
Xie, Zhi
author_sort Wu, Cheng
collection PubMed
description Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. It is known that the tumor microenvironment (TME) regulates tumorigenesis and metastasis. However, how the malignant progression in RB is determined by the heterogeneity of tumor cells and TME remains uncharacterized. Here, we conducted integrative single-cell transcriptome and whole-exome sequencing analysis of RB patients with detailed pathological and clinical measurements. By single-cell transcriptomic sequencing, we profiled around 70,000 cells from tumor samples of seven RB patients. We identified that the major cell types in RB were cone precursor-like (CP-like) and MKI67+ cone precursor (MKI67+ CP) cells. By integrating copy number variation (CNV) analysis, we found that RB samples had large clonal heterogeneity, where the malignant MKI67+ CP cells had significantly larger copy number changes. Enrichment analysis revealed that the conversion of CP-like to MKI67+ CP resulted in the loss of photoreceptor function and increased cell proliferation ability. The TME in RB was composed of tumor-associated macrophages (TAMs), astrocyte-like, and cancer-associated fibroblasts (CAFs). Particularly, during the invasion process, TAMs created an immunosuppressive environment, in which the proportion of TAMs decreased, M1-type macrophage was lost, and the TAMs-related immune functions were depressed. Finally, we identified that TAMs regulated tumor cells through GRN and MIF signaling pathways, while TAMs self-regulated through inhibition of CCL and GALECTIN signaling pathways during the invasion process. Altogether, our study creates a detailed transcriptomic map of RB with single-cell characterization of malignant phenotypes and provides novel molecular insights into the occurrence and progression of RB.
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spelling pubmed-90766572022-05-08 Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma Wu, Cheng Yang, Jiaqi Xiao, Wei Jiang, Zehang Chen, Shuxia Guo, Dianlei Zhang, Ping Liu, Chunqiao Yang, Huasheng Xie, Zhi Cell Death Dis Article Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. It is known that the tumor microenvironment (TME) regulates tumorigenesis and metastasis. However, how the malignant progression in RB is determined by the heterogeneity of tumor cells and TME remains uncharacterized. Here, we conducted integrative single-cell transcriptome and whole-exome sequencing analysis of RB patients with detailed pathological and clinical measurements. By single-cell transcriptomic sequencing, we profiled around 70,000 cells from tumor samples of seven RB patients. We identified that the major cell types in RB were cone precursor-like (CP-like) and MKI67+ cone precursor (MKI67+ CP) cells. By integrating copy number variation (CNV) analysis, we found that RB samples had large clonal heterogeneity, where the malignant MKI67+ CP cells had significantly larger copy number changes. Enrichment analysis revealed that the conversion of CP-like to MKI67+ CP resulted in the loss of photoreceptor function and increased cell proliferation ability. The TME in RB was composed of tumor-associated macrophages (TAMs), astrocyte-like, and cancer-associated fibroblasts (CAFs). Particularly, during the invasion process, TAMs created an immunosuppressive environment, in which the proportion of TAMs decreased, M1-type macrophage was lost, and the TAMs-related immune functions were depressed. Finally, we identified that TAMs regulated tumor cells through GRN and MIF signaling pathways, while TAMs self-regulated through inhibition of CCL and GALECTIN signaling pathways during the invasion process. Altogether, our study creates a detailed transcriptomic map of RB with single-cell characterization of malignant phenotypes and provides novel molecular insights into the occurrence and progression of RB. Nature Publishing Group UK 2022-05-06 /pmc/articles/PMC9076657/ /pubmed/35523772 http://dx.doi.org/10.1038/s41419-022-04904-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wu, Cheng
Yang, Jiaqi
Xiao, Wei
Jiang, Zehang
Chen, Shuxia
Guo, Dianlei
Zhang, Ping
Liu, Chunqiao
Yang, Huasheng
Xie, Zhi
Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title_full Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title_fullStr Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title_full_unstemmed Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title_short Single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
title_sort single-cell characterization of malignant phenotypes and microenvironment alteration in retinoblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076657/
https://www.ncbi.nlm.nih.gov/pubmed/35523772
http://dx.doi.org/10.1038/s41419-022-04904-8
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