» Articles » PMID: 35523772

Single-cell Characterization of Malignant Phenotypes and Microenvironment Alteration in Retinoblastoma

Overview
Journal Cell Death Dis
Date 2022 May 6
PMID 35523772
Authors
Affiliations
Soon will be listed here.
Abstract

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.

Citing Articles

Identification and validation of glycolysis-related diagnostic signatures in diabetic nephropathy: a study based on integrative machine learning and single-cell sequence.

Wu X, Guo B, Chang X, Yang Y, Liu Q, Liu J Front Immunol. 2025; 15:1427626.

PMID: 39916957 PMC: 11798943. DOI: 10.3389/fimmu.2024.1427626.


Oncolytic Viruses and Immunotherapy for the Treatment of Uveal Melanoma and Retinoblastoma: The Current Landscape and Novel Advances.

Kulbay M, Tuli N, Mazza M, Jaffer A, Juntipwong S, Marcotte E Biomedicines. 2025; 13(1).

PMID: 39857692 PMC: 11762644. DOI: 10.3390/biomedicines13010108.


In vitro model of retinoblastoma derived tumor and stromal cells for tumor microenvironment (TME) studies.

Alefeld E, Haase A, Van Meenen D, Budeus B, Drager O, Miroschnikov N Cell Death Dis. 2024; 15(12):905.

PMID: 39695086 PMC: 11655973. DOI: 10.1038/s41419-024-07285-2.


Targeting ALDOA to modulate tumorigenesis and energy metabolism in retinoblastoma.

Wang Y, Tang J, Liu Y, Zhang Z, Zhang H, Ma Y iScience. 2024; 27(9):110725.

PMID: 39262779 PMC: 11388021. DOI: 10.1016/j.isci.2024.110725.


Single-cell RNA-Seq reveals the heterogeneity of fibroblasts within the tympanojugular paraganglioma microenvironment.

Wang S, Zhang B, Lou Z, Hu Y, Wang J, Wang J Heliyon. 2024; 10(15):e35478.

PMID: 39170307 PMC: 11336777. DOI: 10.1016/j.heliyon.2024.e35478.


References
1.
Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

2.
Sun C, Fukui H, Hara K, Zhang X, Kitayama Y, Eda H . FGF9 from cancer-associated fibroblasts is a possible mediator of invasion and anti-apoptosis of gastric cancer cells. BMC Cancer. 2015; 15:333. PMC: 4424580. DOI: 10.1186/s12885-015-1353-3. View

3.
Kanzaki R, Naito H, Kise K, Takara K, Eino D, Minami M . Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy. Sci Rep. 2017; 7(1):10613. PMC: 5587707. DOI: 10.1038/s41598-017-10873-2. View

4.
Pina Y, Boutrid H, Murray T, Jager M, Cebulla C, Schefler A . Impact of tumor-associated macrophages in LH(BETA)T(AG) mice on retinal tumor progression: relation to macrophage subtype. Invest Ophthalmol Vis Sci. 2010; 51(5):2671-7. PMC: 2868494. DOI: 10.1167/iovs.09-4255. View

5.
Voigt A, Whitmore S, Flamme-Wiese M, Riker M, Wiley L, Tucker B . Molecular characterization of foveal versus peripheral human retina by single-cell RNA sequencing. Exp Eye Res. 2019; 184:234-242. PMC: 6596422. DOI: 10.1016/j.exer.2019.05.001. View