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Cited by 62Bioinformatics and Genomic NetworksCutaneous Melanoma Detection and ManagementMelanoma and MAPK Pathways

Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis

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Song, Won-Min, Agrawal, Praveen, Von Itter, Richard, Fontanals-Cirera, Barbara, Wang, Minghui, Zhou, Xianxiao, Mahal, Lara K., Hernando, Eva +1 more·2021·Nature Communications
DOI 10.1038/s41467-021-21457-0PMC PMC7900178
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Abstract

Melanoma is the most lethal skin malignancy, driven by genetic and epigenetic alterations in the complex tumour microenvironment. While large-scale molecular profiling of melanoma has identified molecular signatures associated with melanoma progression, comprehensive systems-level modeling remains elusive. This study builds up predictive gene network models of molecular alterations in primary melanoma by integrating large-scale bulk-based multi-omic and single-cell transcriptomic data. Incorporating clinical, epigenetic, and proteomic data into these networks reveals key subnetworks, cell types, and regulators underlying melanoma progression. Tumors with high immune infiltrates are found to be associated with good prognosis, presumably due to induced CD8+ T-cell cytotoxicity, via MYO1F-mediated M1-polarization of macrophages. Seventeen key drivers of the gene subnetworks associated with poor prognosis, including the transcription factor ZNF180, are tested for their pro-tumorigenic effects in vitro. The anti-tumor effect of silencing ZNF180 is further validated using in vivo xenografts. Experimentally validated targets of ZNF180 are enriched in the ZNF180 centered network and the known pathways such as melanoma cell maintenance and immune cell infiltration. The transcriptional networks and their critical regulators provide insights into the molecular mechanisms of melanomagenesis and pave the way for developing therapeutic strategies for melanoma.

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  • The KND approach has been successfully employed to identify novel pathways and key driver genes of complex human diseases such as AD, Parkinson's disease, melanoma and gastric cancer, and the top drivers predicted for these diseases were experimentally validated in vitro or in vivo.

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    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [44]

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Sorted by citations

Authors
Song, W.-M., Agrawal, P., Von Itter, R., Fontanals-Cirera, B., Wang, M., Zhou, X., Mahal, L. K., Hernando, E., & Zhang, B.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • NYU Langone Health (US)
  • University of Alberta (CA)
Corresponding author
  • Hernando, Eva
  • Zhang, Bin
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-02-22
Volume
12
Issue
1
Pages
1214-1214
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-021-21457-0
PMC
PMC7900178
OpenAlex
W3131231281
Cited by
62
References
10
Citations by year
2026: 2 · 2025: 8 · 2024: 25 · 2023: 14 · 2022: 9 · 2021: 4
FWCI
5.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | National Institutes of Health (U01AG046170, P01CA206980, P50CA225450)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
primary melanoma, tumor microenvironment, gene regulatory networks, MYO1F, M1 macrophage polarization, CD8+ T cell cytotoxicity, immune cell infiltration, melanoma progression, epigenetic modifications, multi-omics integration, single-cell transcriptomics, melanomagenesis, xenografts
MeSH terms
DNA Repair, DNA, Neoplasm, Humans, Interferon-gamma, Melanoma, Models, Biological, Neoplasm Invasiveness, Prognosis, RNA Splicing, RNA, Messenger, Skin Neoplasms, Reproducibility of Results, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Survival Analysis, Gene Silencing, Myosin Type I, Cell Line, Tumor, Gene Regulatory Networks, Tumor Microenvironment

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