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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2, and CD44 through NFκB-signaling

ABSTRACT:

SUBMITTER: Kainulainen K

PROVIDER: S-EPMC11340773 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling

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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP]

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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP-C42B]

Project description:The inflammatory tumor microenvironment (TME) is a key driver of tumor-promoting pro-cesses. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on pros-tate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors up-regulate genes related to stemness while downregulating genes associated with androgen re-sponse in prostate cancer cells. The expression of cancer stem cell plasticity markers NANOG, KLF4, SOX2, OCT4 and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene KLK3 were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2 and CD44 and cancer stem cell plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of cancer stem cell plasticity markers through NFκB signaling pathway.

2024-08-21 | GSE264190 | GEO

Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling

Project description:Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling

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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP]

Project description:Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP]

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Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2 and CD44 through NFκB signaling [LNCaP-C42B]

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M2 macrophages, but not M1 macrophages, support megakaryopoiesis by upregulating PI3K-AKT pathway activity.

Project description:Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

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Unique macrophages different from M1/M2 macrophages inhibit T cell mitogenesis while upregulating Th17 polarization.

Project description:Mycobacterial infection induces suppressor macrophages (MΦs), causing disease exacerbation. There are two major MΦ subsets (M1 and M2 MΦs) that are phenotypically and functionally different. Here, we examined which of the MΦ subsets the mycobacterial infection-induced suppressor MΦs (MIS-MΦs) belong to. MIS-MΦs down-regulated T cell production of Th1 and Th2 cytokines but markedly increased production of interleukin (IL)-17A and IL-22 through up-regulation of Th17 cell expansion. In this phenomenon, a novel MΦ population, which is functionally distinguishable from M1 and M2 MΦ subsets and possesses unique phenotypes (IL-12(+), IL-1β(high), IL-6(+), tumor necrosis factor (TNF)-α(+), nitric oxide synthase (NOS) 2(+), CCR7(high), IL-10(high), arginase (Arg)-1(-), mannose receptor (MR)(low), Ym1(high), Fizz(low), and CD163(high)), played central roles through the action of IL-6 and transforming growth factor (TGF)-β but not IL-21 and IL-23. This new type of MΦ population was induced in infected mice and actively supported the in vivo expansion of Th17 cells.

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SOX2, OCT3/4 and NANOG expression and cellular plasticity in rare human somatic cells requires CD73.

Project description:Endogenous Plastic Somatic (ePS) cells isolated from adult human tissues exhibit extensive lineage plasticity in vitro and in vivo. Here we visualize these rare ePS cells in a latent state, i.e. lacking SOX2, OCT3/4 and NANOG (SON) expression, in non-diseased breast specimens through immunohistochemical analysis of previously identified ePS-specific biomarkers (CD73+, EpCAM+ and CD90-). We also report a novel mechanism by which these latent ePS cells acquire SON expression and plasticity in vitro. Four extracellular factors are necessary for the acquisition of SON expression and lineage plasticity in ePS cells: adenosine (which is produced by the 5' ecto-nucleotidase CD73 and activates in turn the PKA-dependent IL6/STAT3 pathway through the adenosine receptor ADORA2b), IL6, FGF2 and ACTIVIN A. Blocking any pathway component renders ePS cells incapable of SON expression and lineage plasticity. Notably, hESCs do not use adenosine or IL6 nor they express CD73 or ADORA2b and inhibition of adenosine signaling does not ablate their plasticity. Therefore, the data presented here delineate novel circuitry and physiological signals for accessing SON expression in rare, undifferentiated human cells.

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OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells.

Project description:NANOG, OCT4 and SOX2 form the core network of transcription factors supporting embryonic stem (ES) cell self-renewal. While OCT4 and SOX2 expression is relatively uniform, ES cells fluctuate between states of high NANOG expression possessing high self-renewal efficiency, and low NANOG expression exhibiting increased differentiation propensity. NANOG, OCT4 and SOX2 are currently considered to activate transcription of each of the three genes, an architecture that cannot readily account for NANOG heterogeneity. Here, we examine the architecture of the Nanog-centred network using inducible NANOG gain- and loss-of-function approaches. Rather than activating itself, Nanog activity is autorepressive and OCT4/SOX2-independent. Moreover, the influence of Nanog on Oct4 and Sox2 expression is minimal. Using Nanog:GFP reporters, we show that Nanog autorepression is a major regulator of Nanog transcription switching. We conclude that the architecture of the pluripotency gene regulatory network encodes the capacity to generate reversible states of Nanog transcription via a Nanog-centred autorepressive loop. Therefore, cellular variability in self-renewal efficiency is an emergent property of the pluripotency gene regulatory network.

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