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, Matías A.; Adir, Orit; Meshel, Tsipi; Chelladurai, Maharrish; Ryu, Suyeon; Ramos, Romela Irene; Pasmanik‐Chor, Metsada; Hoon, Dave S.B.; Witz, Isaac P.

doi:10.3390/cells12111513

Cited by 6 publications

(14 citation statements)

References 90 publications

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“…This intertumor heterogeneity poses a significant challenge in the clinic as the response to therapy may vary significantly among patients 53 . Previous studies from our lab indicated a significant molecular and functional intertumor heterogeneity among the melanoma cell lines used 17,54‐56 . In contrast to this heterogeneity, all four cell lines employed in the present study underwent cell cycle arrest and cell death after exposure to the Hgb dimer.…”

Section: Discussionmentioning

confidence: 61%

“…53 Previous studies from our lab indicated a significant molecular and functional intertumor heterogeneity among the melanoma cell lines used. 17,[54][55][56] In contrast to this heterogeneity, all four cell lines employed in the present study underwent cell cycle arrest and cell death after exposure to the Hgb dimer. This supports the conclusion that the Hgb dimer can be considered a general inhibitor of melanoma and perhaps other brain-metastasizing cells.…”

Section: Discussionmentioning

confidence: 80%

“…Our lab focuses on the impact of melanoma-brain interactions on melanoma-brain metastasis (MBM) formation, survival, and sustainability. In the present study, we asked if, in addition to several prometastatic melanoma-brain interactions, [14][15][16][17] there are cellular or molecular brain constituents that, when interacting with melanoma cells, could inhibit the formation of MBM or eliminate existing ones. 18,19 In short, human brain metastatic melanoma cells were inoculated subdermally into nude mice to establish the cutaneous (C) variants.…”

Section: Introductionmentioning

confidence: 99%

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A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

Chelladurai,

Xu,

Izraely

et al. 2023

Intl Journal of Cancer

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Metastatic (as well as tumor) microenvironments contain both cancer‐promoting and cancer‐restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung‐derived antimetastatic factor. In the present study, exploring mechanisms regulating melanoma brain metastasis, we discovered that brain‐derived factors restrain proliferation and induce apoptosis and necrosis of brain‐metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that perform these antimetastatic functions. Neither the alpha nor the beta subunit alone was inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer‐induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer‐treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins, playing crucial roles in cancer cell sustainability and progression. Thus, we hypothesize that the hemoglobin dimer functions as a resistance factor against brain‐metastasizing cancer cells.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

Chelladurai,

Xu,

Izraely

et al. 2023

Intl Journal of Cancer

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“…We found that the crosstalk between melanoma and microglia reprograms the phenotype and molecular signature of microglia cells [5]. For example, factors secreted by MBM cells, namely IL-6, induced the STAT3 signaling pathway and increased the expression of suppressor of cytokine signaling 3 (SOCS3) in microglia cells [6]. Inhibition of the JAK/STAT pathway resulted in reduced pro-tumorigenic functions of microglia.…”

Section: Introductionmentioning

confidence: 94%

Heterogeneity in the Metastatic Microenvironment: JunB-Expressing Microglia Cells as Potential Drivers of Melanoma Brain Metastasis Progression

Adir,

Sagi-Assif,

Meshel

et al. 2023

Cancers

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Reciprocal signaling between melanoma brain metastatic (MBM) cells and microglia reprograms the phenotype of both interaction partners, including upregulation of the transcription factor JunB in microglia. Here, we aimed to elucidate the impact of microglial JunB upregulation on MBM progression. For molecular profiling, we employed RNA-seq and reverse-phase protein array (RPPA). To test microglial JunB functions, we generated microglia variants stably overexpressing JunB (JunBhi) or with downregulated levels of JunB (JunBlo). Melanoma-derived factors, namely leukemia inhibitory factor (LIF), controlled JunB upregulation through Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling. The expression levels of JunB in melanoma-associated microglia were heterogeneous. Flow cytometry analysis revealed the existence of basal-level JunB-expressing microglia alongside microglia highly expressing JunB. Proteomic profiling revealed a differential protein expression in JunBhi and JunBlo cells, namely the expression of microglia activation markers Iba-1 and CD150, and the immunosuppressive molecules SOCS3 and PD-L1. Functionally, JunBhi microglia displayed decreased migratory capacity and phagocytic activity. JunBlo microglia reduced melanoma proliferation and migration, while JunBhi microglia preserved the ability of melanoma cells to proliferate in three-dimensional co-cultures, that was abrogated by targeting leukemia inhibitory factor receptor (LIFR) in control microglia–melanoma spheroids. Altogether, these data highlight a melanoma-mediated heterogenous effect on microglial JunB expression, dictating the nature of their functional involvement in MBM progression. Targeting microglia highly expressing JunB may potentially be utilized for MBM theranostics.

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“…For example, melanoma cells can alter astrocytes to promote monocyte chemoattractant protein-1 (MCP-1) production, which in turn drives MBM proliferation and invasion ( 216 ). Microglial JAK/STAT activation from melanoma-secreted IL-6 can similarly enhance MBM progression ( 217 ).…”

Section: Therapeutic Opportunities Against Immune Escape Emt and Earl...mentioning

confidence: 99%

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

Shirley,

Chhabra,

Amiri

et al. 2024

Front. Immunol.

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Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind “dual drivers” simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes.

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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

Cited by 6 publications

References 90 publications

A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent

Heterogeneity in the Metastatic Microenvironment: JunB-Expressing Microglia Cells as Potential Drivers of Melanoma Brain Metastasis Progression

Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy

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