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The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway

Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucida...

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Autores principales: Izraely, Sivan, Ben-Menachem, Shlomit, Malka, Sapir, Sagi-Assif, Orit, Bustos, Matias A., Adir, Orit, Meshel, Tsipi, Chelladurai, Maharrish, Ryu, Suyeon, Ramos, Romela I., Pasmanik-Chor, Metsada, Hoon, Dave S. B., Witz, Isaac P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253015/
https://www.ncbi.nlm.nih.gov/pubmed/37296634
http://dx.doi.org/10.3390/cells12111513
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author Izraely, Sivan
Ben-Menachem, Shlomit
Malka, Sapir
Sagi-Assif, Orit
Bustos, Matias A.
Adir, Orit
Meshel, Tsipi
Chelladurai, Maharrish
Ryu, Suyeon
Ramos, Romela I.
Pasmanik-Chor, Metsada
Hoon, Dave S. B.
Witz, Isaac P.
author_facet Izraely, Sivan
Ben-Menachem, Shlomit
Malka, Sapir
Sagi-Assif, Orit
Bustos, Matias A.
Adir, Orit
Meshel, Tsipi
Chelladurai, Maharrish
Ryu, Suyeon
Ramos, Romela I.
Pasmanik-Chor, Metsada
Hoon, Dave S. B.
Witz, Isaac P.
author_sort Izraely, Sivan
collection PubMed
description Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas.
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spelling pubmed-102530152023-06-10 The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway Izraely, Sivan Ben-Menachem, Shlomit Malka, Sapir Sagi-Assif, Orit Bustos, Matias A. Adir, Orit Meshel, Tsipi Chelladurai, Maharrish Ryu, Suyeon Ramos, Romela I. Pasmanik-Chor, Metsada Hoon, Dave S. B. Witz, Isaac P. Cells Article Previous studies from our lab demonstrated that the crosstalk between brain-metastasizing melanoma cells and microglia, the macrophage-like cells of the central nervous system, fuels progression to metastasis. In the present study, an in-depth investigation of melanoma-microglia interactions elucidated a pro-metastatic molecular mechanism that drives a vicious melanoma-brain-metastasis cycle. We employed RNA-Sequencing, HTG miRNA whole transcriptome assay, and reverse phase protein arrays (RPPA) to analyze the impact of melanoma-microglia interactions on sustainability and progression of four different human brain-metastasizing melanoma cell lines. Microglia cells exposed to melanoma-derived IL-6 exhibited upregulated levels of STAT3 phosphorylation and SOCS3 expression, which, in turn, promoted melanoma cell viability and metastatic potential. IL-6/STAT3 pathway inhibitors diminished the pro-metastatic functions of microglia and reduced melanoma progression. SOCS3 overexpression in microglia cells evoked microglial support in melanoma brain metastasis by increasing melanoma cell migration and proliferation. Different melanomas exhibited heterogeneity in their microglia-activating capacity as well as in their response to microglia-derived signals. In spite of this reality and based on the results of the present study, we concluded that the activation of the IL-6/STAT3/SOCS3 pathway in microglia is a major mechanism by which reciprocal melanoma-microglia signaling engineers the interacting microglia to reinforce the progression of melanoma brain metastasis. This mechanism may operate differently in different melanomas. MDPI 2023-05-30 /pmc/articles/PMC10253015/ /pubmed/37296634 http://dx.doi.org/10.3390/cells12111513 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Izraely, Sivan
Ben-Menachem, Shlomit
Malka, Sapir
Sagi-Assif, Orit
Bustos, Matias A.
Adir, Orit
Meshel, Tsipi
Chelladurai, Maharrish
Ryu, Suyeon
Ramos, Romela I.
Pasmanik-Chor, Metsada
Hoon, Dave S. B.
Witz, Isaac P.
The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title_full The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title_fullStr The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title_full_unstemmed The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title_short The Vicious Cycle of Melanoma-Microglia Crosstalk: Inter-Melanoma Variations in the Brain-Metastasis-Promoting IL-6/JAK/STAT3 Signaling Pathway
title_sort vicious cycle of melanoma-microglia crosstalk: inter-melanoma variations in the brain-metastasis-promoting il-6/jak/stat3 signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253015/
https://www.ncbi.nlm.nih.gov/pubmed/37296634
http://dx.doi.org/10.3390/cells12111513
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