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

Publication Title

Cells

Authors

Sivan Izraely
Shlomit Ben-Menachem
Sapir Malka
Orit Sagi-Assif
Matias A Bustos, Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA 90404, USAFollow
Orit Adir
Tsipi Meshel
Maharrish Chelladurai
Suyeon Ryu, Department of Genome Sequencing, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA 90404, USAFollow
Romela Irene Ramos, Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA 90404, USAFollow
Metsada Pasmanik-Chor
Dave S B Hoon, Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA 90404, USAFollow
Isaac P Witz

Document Type

Article

Publication Date

5-30-2023

Keywords

california; sjci; genomics; IL-6; SOCS3; STAT3; brain metastasis; inter-tumor heterogeneity; melanoma; microglia; Humans; Microglia; Interleukin-6; Signal Transduction; Suppressor of Cytokine Signaling Proteins; Melanoma; Brain Neoplasms; Brain; STAT3 Transcription Factor

Abstract

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.

Area of Special Interest

Cancer

Area of Special Interest

Neurosciences (Brain & Spine)

Specialty/Research Institute

Oncology

Specialty/Research Institute

Neurosciences

DOI

10.3390/cells12111513