M1 Macrophages Induce Protumor Inflammation in Melanoma Cells through TNFR–NF-κB Signaling

Kainulainen, Kirsi; Takabe, Piia; Heikkinen, Sami; Aaltonen, Niina; Motte, Carol de la; Rauhala, Leena; Durst, Franziska C; Oikari, Sanna; Hukkanen, Taija; Rahunen, Eija; Ikonen, Ella; Hartikainen, Jaana M.; Ketola, Kirsi; Pasonen‐Seppänen, Sanna

doi:10.1016/j.jid.2022.04.024

Cited by 13 publications

(13 citation statements)

References 68 publications

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“…www.nature.com/scientificreports/ Mono-cultured THP-1 macrophages captured by scanning electron microscopy (SEM) exhibited a clear morphological difference of M1-type compared to M0 (naïve) and M2 types. Consistent with a previous report 24 , M1-type macrophages showed elongated, spindle-like structures with prominent pseudopods, unlike spherical, smoother structures of M0 and M2 types (Fig. 4A-C).…”

Section: Sep Treatment Of Co-cultures Elevated the Thickness And Inte...supporting

confidence: 93%

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Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity

Beamer

Zamora

Nestor-Kalinoski

et al. 2023

Sci Rep

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Gut mucosa consists of stratified layers of microbes, semi-permeable mucus, epithelium and stroma abundant in immune cells. Although tightly regulated, interactions between gut commensals and immune cells play indispensable roles in homeostasis and cancer pathogenesis in the body. Thus, there is a critical need to develop a robust model for the gut mucosal microenvironment. Here, we report our novel co-culture utilizing 3D Flipwell system for establishing the stratified layers of discrete mucosal components. This method allows for analyzing synchronous effects of test stimuli on gut bacteria, mucus, epithelium and immune cells, as well as their crosstalks. In the present report, we tested the immuno-stimulatory effects of sepiapterin (SEP, the precursor of the cofactor of nitric oxide synthase (NOS)—BH4) on the gut mucosal community. We previously reported that SEP effectively reprogrammed tumor-associated macrophages and inhibited breast tumor cell growth. In our co-cultures, SEP largely promoted mucus integrity, bacterial binding, and M1-like polarization of macrophages. Conversely, these phenomena were absent in control-treated cultures. Our results demonstrate that this novel co-culture may serve as a robust in vitro system to recapitulate the effects of pharmacological agents on the gut mucosal microenvironment, and could potentially be expanded to test the effects outside the gut.

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Section: Sep Treatment Of Co-cultures Elevated the Thickness And Inte...supporting

confidence: 93%

“…In contrast, after SEP treatment, these macrophages acquired spindle-like structures with numerous pseudopods, similar to M1-type macrophages (Fig. 4 B,S,T) 24 . This observation was consistent with previous reports that high doses of certain probiotics, such as Bacillus subtilis , could induce M1 polarization of macrophages 30 , 31 .…”

Section: Resultsmentioning

confidence: 64%

Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity

Beamer

Zamora

Nestor-Kalinoski

et al. 2023

Sci Rep

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“…Additionally, we assessed the effect of conditioned media (CM) of THP-1 macrophages polarized to proinflammatory M1 or immunosuppressive M2 subtypes (Kainulainen et al , 2022) on apoptosis in transduced A549 cells. The CM from M1 polarized THP-1 cells contains TNFα and other proinflammatory cytokines (Kainulainen et al , 2022). M1 CM treated cells with KEAP1 wt showed increased caspase 3/7 staining, which was substantially attenuated with KEAP1 R320Q or R470C mutants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells

Deen,

Adinolfi,

Härkönen

et al. 2023

Preprint

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The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2-related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) - Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and the mutants was employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.

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“…But this theory is challenged: M1/M2 polarization is an oversimplification which can't show the heterogenous TAMs plasticity. Very recently, evidence showed that M1 macrophages induce pro-tumor inflammation in melanoma cells via TNFR-NF-κB signaling [23]. Also fibroblasts in the tumor also could induce trans-differentiation, from anti-tumorigenic macrophages to pro-tumor TAMs [24].…”

Section: Discussionmentioning

confidence: 99%

Tumor-associated macrophages in direct contact with prostate cancer cells promote malignant proliferation and metastasis through NOTCH1 pathway

Shi¹,

Sun²,

Zhou³

et al. 2022

Int. J. Biol. Sci.

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Background: M2 macrophages are well accepted to promote cancer progression in the prostate cancer (PCa). Paracrine is the principally studied mode of communication between M2 macrophages and tumor cells. In addition to this, we present here a novel model to demonstrate these cellular communications. Methods: PCa cells were co-cultured with THP-1/ human peripheral blood mononuclear cells derived M2 macrophages in direct contact manner. Cancer cell proliferation and invasion were examined to explain how direct contact communicates. Cell-based findings were validated in two xenograft models and patients samples. Results: M2 macrophage direct contact induced a higher proliferation and invasion in PCa cells when compared with noncontact coculture manner. In direct contact manner, NOTCH1 pathway was greatly activated in PCa cells, induced by elevated γ-secretase activity and higher coactivator MAML2 expression. Additionally, blocking γ-secretase activity and depletion of MAML2 completely abolished M2 macrophage direct contact-mediated PCa cell proliferation and invasion. In vivo, inhibiting NOTCH1 signalling impaired M2 macrophage-mediated PCa tumor growth and lung metastasis. Notably, M2 macrophage infiltration as well as high NOTCH1 signaling in cancer cells indicated more aggressive features and worse survival in PCa patients. Conclusion:Our results demonstrated the cell-cell direct contact pattern is an important way in PCa microenvironment cell communication. In this manner, elevated γ-secretase activity and MAML2 expression induced higher NOTCH1 signalling in PCa cells, which increased tumor cells proliferation and invasion. This potentially provided a therapeutic target for PCa.

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M1 Macrophages Induce Protumor Inflammation in Melanoma Cells through TNFR–NF-κB Signaling

Cited by 13 publications

References 68 publications

Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity

Novel 3D Flipwell system that models gut mucosal microenvironment for studying interactions between gut microbiota, epithelia and immunity

Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells

Tumor-associated macrophages in direct contact with prostate cancer cells promote malignant proliferation and metastasis through NOTCH1 pathway

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