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

Won-Min Song, Praveen Agrawal, Richard Von Itter, Barbara Fontanals-Cirera, Minghui Wang, Xianxiao Zhou, Lara K. Mahal, Eva Hernando () and Bin Zhang ()
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Won-Min Song: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Praveen Agrawal: NYU Grossman School of Medicine
Richard Von Itter: NYU Grossman School of Medicine
Barbara Fontanals-Cirera: NYU Grossman School of Medicine
Minghui Wang: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Xianxiao Zhou: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place
Lara K. Mahal: University of Alberta
Eva Hernando: NYU Grossman School of Medicine
Bin Zhang: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21457-0

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