Research progress of single-cell transcriptome sequencing in uveal melanoma_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhao Hanqing , Luo Jingting , Li Yang ,  Wei Wenbin

Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China;

Corresponding author：

Wei Wenbin, Email: weiwenbintr@163.com

Keywords：

Uveal Neoplasms; Melanoma; Tumor Microenvironment; Transcriptome; Review

DOI：

10.3760/cma.j.cn511434-20220130-00063

Video：

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Uveal melanoma (UM) is an aggressive and lethal tumor in the eye. The complexity and heterogeneity of UM and its microenvironment leads to a lack of strategies for early prevention and treatment of metastases. Single-cell sequencing technologies provide critical insights into deciphering the complexity of intratumor heterogeneity and the microenvironment by enabling genomic, transcriptomic, and epigenetic analysis at the single-cell level. With the help of bioinformatics analysis combined with artificial intelligence algorithms, molecular indicator systems related to prognosis as well as therapeutic targets can be found, which can provide a basis for guiding the selection of clinical treatment plans. However, the single-cell sequencing technology also has certain limitations, such as high sample requirements, expensive and time-consuming sequencing. It is believed that with the improvement of science and technology and the update of analytical methods, these shortcomings can be gradually solved, and this rare tumor will eventually be overcome in the future, and the goal of long-term survival of UM patients will be achieved.

Citation： Zhao Hanqing, Luo Jingting, Li Yang, Wei Wenbin. Research progress of single-cell transcriptome sequencing in uveal melanoma. Chinese Journal of Ocular Fundus Diseases, 2022, 38(3): 248-252. doi: 10.3760/cma.j.cn511434-20220130-00063 Copy

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4.	Kaliki S, Shields CL. Uveal melanoma: relatively rare but deadly cancer[J]. Eye (Lond), 2017, 31(2): 241-257. DOI: 10.1038/eye.2016.275.
5.	张路遥, 时永全. 单细胞测序技术在消化系统肿瘤研究中的应用及进展[J]. 西南国防医药, 2020, 30(11): 1032-1035. DOI: 10.3969/j.issn.1004-0188.2020.11.019.Zhang LY, Shi YQ. Application and progress of single-cell sequencing technology in digestive system tumor research[J]. Medical Journal of National Defending Forces in Southwest China, 2020, 30(11): 1032-1035. DOI: 10.3969/j.issn.1004-0188.2020.11.019.
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9.	Tang F, Barbacioru C, Wang Y, et al. mRNA-Seq whole-transcriptome analysis of a single cell[J]. Nat Methods, 2009, 6(5): 377-382. DOI: 10.1038/nmeth.1315.
10.	Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity[J]. Nature, 2013, 501(7467): 328-337. DOI: 10.1038/nature12624.
11.	Durante MA, Rodriguez DA, Kurtenbach S, et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma[J]. Nat Commun, 2020, 11(1): 496. DOI: 10.1038/s41467-019-14256-1.
12.	Pandiani C, Strub T, Nottet N, et al. Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease[J]. Cell Death Differ, 2021, 28(6): 1990-2000. DOI: 10.1038/s41418-020-00730-7.
13.	Strub T, Martel A, Nahon-Esteve S, et al. Translation of single-cell transcriptomic analysis of uveal melanomas to clinical oncology[J/OL]. Prog Retin Eye Res, 2021, 85: 100968[2021-04-15].https://pubmed.ncbi.nlm.nih.gov/33852963/. DOI: 10.1016/j.preteyeres.2021.100968.
14.	杨芳, 于雁. 肿瘤微环境-肿瘤转移的关键因素[J]. 中国肺癌杂志, 2015, 18(1): 48-54. DOI: 10.3779/j.issn.1009-3419.2015.01.08.Yang F, Yu Y. Tumor microenvironment-the critical element of tumor metastasis[J]. Chin J Lung Cancer, 2015, 18(1): 48-54. DOI: 10.3779/j.issn.1009-3419.2015.01.08.
15.	Wang Y, Xu Y, Dai X, et al. The prognostic landscape of adaptive immune resistance signatures and infiltrating immune cells in the tumor microenvironment of uveal melanoma[J/OL]. Exp Eye Res, 2020, 196: 108069[2020-05-19]. https://pubmed.ncbi.nlm.nih.gov/32439398/. DOI: 10.1016/j.exer.2020.108069.
16.	Tosi A, Cappellesso R, Dei Tos AP, et al. The immune cell landscape of metastatic uveal melanoma correlates with overall survival[J]. J Exp Clin Cancer Res, 2021, 40(1): 154. DOI: 10.1186/s13046-021-01947-1.
17.	Bronkhorst IH, Vu TH, Jordanova ES, et al. Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2012, 53(9): 5370-5378. DOI: 10.1167/iovs.11-9280.
18.	Triozzi PL, Schoenfield L, Plesec T, et al. Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes[J/OL]. Oncoimmunology, 2014, 8(10): e947169[2014-10-31]. https://pubmed.ncbi.nlm.nih.gov/31646061/. DOI: 10.4161/21624011.2014.947169.
19.	Gezgin G, Dogrusöz M, van Essen TH, et al. Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment[J]. Cancer Immunol Immunother, 2017, 66(7): 903-912. DOI: 10.1007/s00262-017-1991-1.
20.	Lin W, Beasley AB, Ardakani NM, et al. Intra-and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing[J/OL]. Cold Spring Harb Mol Case Stud, 2021, 7(5): a006111[2021-10-19]. https://pubmed.ncbi.nlm.nih.gov/34470851/. DOI: 10.1101/mcs.a006111.
21.	Shain AH, Bagger MM, Yu R, et al. The genetic evolution of metastatic uveal melanoma[J]. Nat Genet, 2019, 51(7): 1123-1130. DOI: 10.1038/s41588-019-0440-9.
22.	Bakhoum MF, Francis JH, Agustinus A, et al. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression[J/OL]. Nat Commun, 2021, 12(1): 5402[2021-09-13]. https://pubmed.ncbi.nlm.nih.gov/34518527/. DOI: 10.1038/s41467-021-25529-z.
23.	Medina CA, Biscotti CV, Singh N, et al. Diagnostic cytologic features of uveal melanoma[J]. Ophthalmology, 2015, 122(8): 1580-1584. DOI: 10.1016/j.ophtha.2015.04.013.
24.	Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging[J]. CA Cancer J Clin, 2017, 67(2): 93-99. DOI: 10.3322/caac.21388.
25.	Ewens KG, Kanetsky PA, Richards-Yutz J, et al. Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome[J]. Investig Ophthalmol Vis Sci, 2013, 54(8): 5721-5729. DOI: 10.1167/iovs.13-12195.
26.	Dogrusöz M, Bagger M, Van Duinen SG, et al. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status[J]. Investig Ophthalmol Vis Sci, 2017, 58(2): 833-842. DOI: 10.1167/iovs.16-20212.
27.	Bagger M, Andersen MT, Andersen KK, et al. The prognostic effect of American Joint Committee on Cancer staging and genetic status in patients with choroidal and ciliary body melanoma[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 438-444. DOI: 10.1167/iovs.14-15571.
28.	Onken MD, Worley LA, Ehlers JP, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death[J]. Cancer Res, 2004, 64(20): 7205-7209. DOI: 10.1158/0008-5472.CAN-04-1750.
29.	Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma[J]. Nat Commun, 2018, 9(1): 116. DOI: 10.1038/s41467-017-02428-w.
30.	Li Y, Yang X, Yang J, et al. An 11-gene-based prognostic signature for uveal melanoma metastasis based on gene expression and DNA methylation profile[J]. J Cell Biochem, 2019, 120: 8630-8639. DOI: 10.1002/jcb.28151.
31.	van Essen TH, van Pelt SI, Bronkhorst IH, et al. Upregulation of HLA expression in primary uveal melanoma by infiltrating leukocytes[J/OL]. PLoS One, 2016, 11(10): e0164292[2016-10-20]. https://pubmed.ncbi.nlm.nih.gov/27764126/. DOI: 10.1371/journal.pone.0164292.
32.	Liu Z, Li S, Huang S, et al. N6-methyladenosine regulators and related lncRNAs are potential to be prognostic markers for uveal melanoma and indicators of tumor microenvironment remodeling[J/OL]. Front Oncol, 2021, 11: 704543[2021-07-30]. https://pubmed.ncbi.nlm.nih.gov/34395276/. DOI: 10.3389/fonc.2021.704543.
33.	Bartlett EK, Fetsch PA, Filie AC, et al. Human melanoma metastases demonstrate nonstochastic site-specific antigen heterogeneity that correlates with T-cell infiltration[J]. Clin Cancer Res, 2014, 20(10): 2607-2616. DOI: 10.1158/1078-0432.CCR-13-2690.
34.	Sun Y, Wu J, Yuan Y, et al. Construction of a promising tumor-infiltrating CD8⁺ T cells gene signature to improve prediction of the prognosis and immune response of uveal melanoma[J/OL]. Front Cell Dev Biol, 2021, 9: 673838[2021-05-28]. https://pubmed.ncbi.nlm.nih.gov/34124058/. DOI: 10.3389/fcell.2021.673838.
35.	Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma[J]. Cancer Treat Rev, 2012, 38(5): 549-553. DOI: 10.1016/j.ctrv.2012.01.002.
36.	Singh RK, Gupta S, Dastidar S, et al. Cysteinyl leukotrienes and their receptors: molecular and functional characteristics[J]. Pharmacology, 2010, 85(6): 336-349. DOI: 10.1159/000312669.
37.	Gusach A, Luginina A, Marin E, et al. Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors[J/OL]. Nat Commun, 2019, 10(1): 5573[2019-12-06]. https://pubmed.ncbi.nlm.nih.gov/31811124/. DOI: 10.1038/s41467-019-13348-2.
38.	Nell RJ, Menger NV, Versluis M, et al. Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma[J]. BMC Cancer, 2021, 21(1): 164. DOI: 10.1186/s12885-021-07865-x.

1. Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival[J]. Ophthalmology, 2011, 118(9): 1881-1885. DOI: 10.1016/j.ophtha.2011.01.040.
2. Shields CL, Kaliki S, Shah SU, et al. Iris melanoma: features and prognosis in 317 children and adults[J]. J AAPOS, 2012, 16(1): 10-16. DOI: 10.1016/j.jaapos.2011.10.012.
3. Hoefsmit EP, Rozeman EA, Van TM, et al. Comprehensive analysis of cutaneous and uveal melanoma liver metastases[J/OL]. J Immunother Cancer, 2020, 8(2): e001501[2020-12-01]. https://pubmed.ncbi.nlm.nih.gov/33262254/. DOI: 10.1136/jitc-2020-001501.
4. Kaliki S, Shields CL. Uveal melanoma: relatively rare but deadly cancer[J]. Eye (Lond), 2017, 31(2): 241-257. DOI: 10.1038/eye.2016.275.
5. 张路遥, 时永全. 单细胞测序技术在消化系统肿瘤研究中的应用及进展[J]. 西南国防医药, 2020, 30(11): 1032-1035. DOI: 10.3969/j.issn.1004-0188.2020.11.019.Zhang LY, Shi YQ. Application and progress of single-cell sequencing technology in digestive system tumor research[J]. Medical Journal of National Defending Forces in Southwest China, 2020, 30(11): 1032-1035. DOI: 10.3969/j.issn.1004-0188.2020.11.019.
6. Robertson AG, Shih J, Yau C, et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma[J]. Cancer Cell, 2018, 33(1): 151. DOI: 10.1016/j.ccell.2017.07.003.
7. Pan H, Lu L, Cui J, et al. Immunological analyses reveal an immune subtype of uveal melanoma with a poor prognosis[J]. Aging (Albany NY), 2020, 12(2): 1446-1464. DOI: 10.18632/aging.102693.
8. Zhao H, Chen Y, Shen P, et al. Identification of immune cell infiltration landscape and their prognostic significance in uveal melanoma[J/OL]. Front Cell Dev Biol, 2021, 9: 713569[2021-08-26]. https://pubmed.ncbi.nlm.nih.gov/34513843/. DOI: 10.3389/fcell.2021.713569.
9. Tang F, Barbacioru C, Wang Y, et al. mRNA-Seq whole-transcriptome analysis of a single cell[J]. Nat Methods, 2009, 6(5): 377-382. DOI: 10.1038/nmeth.1315.
10. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity[J]. Nature, 2013, 501(7467): 328-337. DOI: 10.1038/nature12624.
11. Durante MA, Rodriguez DA, Kurtenbach S, et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma[J]. Nat Commun, 2020, 11(1): 496. DOI: 10.1038/s41467-019-14256-1.
12. Pandiani C, Strub T, Nottet N, et al. Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease[J]. Cell Death Differ, 2021, 28(6): 1990-2000. DOI: 10.1038/s41418-020-00730-7.
13. Strub T, Martel A, Nahon-Esteve S, et al. Translation of single-cell transcriptomic analysis of uveal melanomas to clinical oncology[J/OL]. Prog Retin Eye Res, 2021, 85: 100968[2021-04-15].https://pubmed.ncbi.nlm.nih.gov/33852963/. DOI: 10.1016/j.preteyeres.2021.100968.
14. 杨芳, 于雁. 肿瘤微环境-肿瘤转移的关键因素[J]. 中国肺癌杂志, 2015, 18(1): 48-54. DOI: 10.3779/j.issn.1009-3419.2015.01.08.Yang F, Yu Y. Tumor microenvironment-the critical element of tumor metastasis[J]. Chin J Lung Cancer, 2015, 18(1): 48-54. DOI: 10.3779/j.issn.1009-3419.2015.01.08.
15. Wang Y, Xu Y, Dai X, et al. The prognostic landscape of adaptive immune resistance signatures and infiltrating immune cells in the tumor microenvironment of uveal melanoma[J/OL]. Exp Eye Res, 2020, 196: 108069[2020-05-19]. https://pubmed.ncbi.nlm.nih.gov/32439398/. DOI: 10.1016/j.exer.2020.108069.
16. Tosi A, Cappellesso R, Dei Tos AP, et al. The immune cell landscape of metastatic uveal melanoma correlates with overall survival[J]. J Exp Clin Cancer Res, 2021, 40(1): 154. DOI: 10.1186/s13046-021-01947-1.
17. Bronkhorst IH, Vu TH, Jordanova ES, et al. Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma[J]. Invest Ophthalmol Vis Sci, 2012, 53(9): 5370-5378. DOI: 10.1167/iovs.11-9280.
18. Triozzi PL, Schoenfield L, Plesec T, et al. Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes[J/OL]. Oncoimmunology, 2014, 8(10): e947169[2014-10-31]. https://pubmed.ncbi.nlm.nih.gov/31646061/. DOI: 10.4161/21624011.2014.947169.
19. Gezgin G, Dogrusöz M, van Essen TH, et al. Genetic evolution of uveal melanoma guides the development of an inflammatory microenvironment[J]. Cancer Immunol Immunother, 2017, 66(7): 903-912. DOI: 10.1007/s00262-017-1991-1.
20. Lin W, Beasley AB, Ardakani NM, et al. Intra-and intertumoral heterogeneity of liver metastases in a patient with uveal melanoma revealed by single-cell RNA sequencing[J/OL]. Cold Spring Harb Mol Case Stud, 2021, 7(5): a006111[2021-10-19]. https://pubmed.ncbi.nlm.nih.gov/34470851/. DOI: 10.1101/mcs.a006111.
21. Shain AH, Bagger MM, Yu R, et al. The genetic evolution of metastatic uveal melanoma[J]. Nat Genet, 2019, 51(7): 1123-1130. DOI: 10.1038/s41588-019-0440-9.
22. Bakhoum MF, Francis JH, Agustinus A, et al. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression[J/OL]. Nat Commun, 2021, 12(1): 5402[2021-09-13]. https://pubmed.ncbi.nlm.nih.gov/34518527/. DOI: 10.1038/s41467-021-25529-z.
23. Medina CA, Biscotti CV, Singh N, et al. Diagnostic cytologic features of uveal melanoma[J]. Ophthalmology, 2015, 122(8): 1580-1584. DOI: 10.1016/j.ophtha.2015.04.013.
24. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging[J]. CA Cancer J Clin, 2017, 67(2): 93-99. DOI: 10.3322/caac.21388.
25. Ewens KG, Kanetsky PA, Richards-Yutz J, et al. Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome[J]. Investig Ophthalmol Vis Sci, 2013, 54(8): 5721-5729. DOI: 10.1167/iovs.13-12195.
26. Dogrusöz M, Bagger M, Van Duinen SG, et al. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status[J]. Investig Ophthalmol Vis Sci, 2017, 58(2): 833-842. DOI: 10.1167/iovs.16-20212.
27. Bagger M, Andersen MT, Andersen KK, et al. The prognostic effect of American Joint Committee on Cancer staging and genetic status in patients with choroidal and ciliary body melanoma[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 438-444. DOI: 10.1167/iovs.14-15571.
28. Onken MD, Worley LA, Ehlers JP, et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death[J]. Cancer Res, 2004, 64(20): 7205-7209. DOI: 10.1158/0008-5472.CAN-04-1750.
29. Field MG, Durante MA, Anbunathan H, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma[J]. Nat Commun, 2018, 9(1): 116. DOI: 10.1038/s41467-017-02428-w.
30. Li Y, Yang X, Yang J, et al. An 11-gene-based prognostic signature for uveal melanoma metastasis based on gene expression and DNA methylation profile[J]. J Cell Biochem, 2019, 120: 8630-8639. DOI: 10.1002/jcb.28151.
31. van Essen TH, van Pelt SI, Bronkhorst IH, et al. Upregulation of HLA expression in primary uveal melanoma by infiltrating leukocytes[J/OL]. PLoS One, 2016, 11(10): e0164292[2016-10-20]. https://pubmed.ncbi.nlm.nih.gov/27764126/. DOI: 10.1371/journal.pone.0164292.
32. Liu Z, Li S, Huang S, et al. N6-methyladenosine regulators and related lncRNAs are potential to be prognostic markers for uveal melanoma and indicators of tumor microenvironment remodeling[J/OL]. Front Oncol, 2021, 11: 704543[2021-07-30]. https://pubmed.ncbi.nlm.nih.gov/34395276/. DOI: 10.3389/fonc.2021.704543.
33. Bartlett EK, Fetsch PA, Filie AC, et al. Human melanoma metastases demonstrate nonstochastic site-specific antigen heterogeneity that correlates with T-cell infiltration[J]. Clin Cancer Res, 2014, 20(10): 2607-2616. DOI: 10.1158/1078-0432.CCR-13-2690.
34. Sun Y, Wu J, Yuan Y, et al. Construction of a promising tumor-infiltrating CD8⁺ T cells gene signature to improve prediction of the prognosis and immune response of uveal melanoma[J/OL]. Front Cell Dev Biol, 2021, 9: 673838[2021-05-28]. https://pubmed.ncbi.nlm.nih.gov/34124058/. DOI: 10.3389/fcell.2021.673838.
35. Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma[J]. Cancer Treat Rev, 2012, 38(5): 549-553. DOI: 10.1016/j.ctrv.2012.01.002.
36. Singh RK, Gupta S, Dastidar S, et al. Cysteinyl leukotrienes and their receptors: molecular and functional characteristics[J]. Pharmacology, 2010, 85(6): 336-349. DOI: 10.1159/000312669.
37. Gusach A, Luginina A, Marin E, et al. Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors[J/OL]. Nat Commun, 2019, 10(1): 5573[2019-12-06]. https://pubmed.ncbi.nlm.nih.gov/31811124/. DOI: 10.1038/s41467-019-13348-2.
38. Nell RJ, Menger NV, Versluis M, et al. Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma[J]. BMC Cancer, 2021, 21(1): 164. DOI: 10.1186/s12885-021-07865-x.

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