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Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors

ABSTRACT: Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE218138 | GEO | 2023/04/03

REPOSITORIES: GEO

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JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

Project description:Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the tumor microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using in vitro and in vivo models, we find that tumor-derived factors induce activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in macrophages. We also demonstrate that loss of STAT3 in myeloid cells leads to enhanced mammary tumorigenesis. Further studies show that macrophages contribute to resistance of mammary tumors to the JAK/STAT inhibitor ruxolitinib in vivo and that ruxolitinib-treated macrophages produce soluble factors that promote resistance of tumor cells to JAK inhibition in vitro. Finally, we demonstrate that STAT3 deletion and JAK/STAT inhibition in macrophages increases expression of the pro-tumorigenic factor cyclooxygenase-2 (COX-2) and that COX-2 inhibition enhances responsiveness of tumors to ruxolitinib. These findings define a novel mechanism through which macrophages promote therapeutic resistance and highlight the importance of understanding the impact of targeted therapies on the tumor microenvironment.

2019-05-16 | GSE131300 | GEO

Retinoic acid inhibits tumor-associated mesenchymal stromal cell transformation in melanoma

Project description:Bone marrow mesenchymal stem/stromal cells (BMSCs) can be transformed into tumor-associated MSCs (TA-MSCs) within the tumor microenvironment to facilitate tumor progression. However, the underline mechanism and potential therapeutic strategy remain unclear. Here, we explored that interleukin 17 (IL-17) cooperating with IFNγ transforms BMSCs into TA-MSCs, which promotes tumor progression by recruiting macrophages/monocytes and myeloid-derived suppressor cells (MDSCs) in murine melanoma. IL-17 and IFNγ transformed TA-MSCs have high expression levels of myelocyte-recruiting chemokines (CCL2, CCL5, CCL7, and CCL20) mediated by activated NF-κB signaling pathway. Furthermore, retinoic acid inhibits NF-κB signaling, decreases chemokine expression, and suppresses the tumor-promoting function of transformed TA-MSCs by prohibiting the recruitment of macrophages/monocytes and MDSCs in the tumor microenvironment. Overall, our findings demonstrate that IL-17 collaborating with IFNγ to induce TA-MSC transformation, which can be targeted by RA for melanoma treatment.

2021-03-19 | GSE169145 | GEO

Global interactome mapping reveals pro-cancerous interactions of NF-κB in breast cancer

Project description:NF-κB has an essential role in innate immune response and inflammation and is involved in cancer development and progression. We apply the SEC-PCP-SILAC method incorporating metabolic labeling, size exclusion chromatography and protein correlation profiling to construct a complex network of interactome rearrangement in response to NF-κB modulation in breast cancer cells. Our interaction network represents a complex insight into the dynamics of MCF-7 protein interactome associated with NF-κB pathway. Our dataset could serve as a basis for future studies characterizing role of NF-κB in breast cancer cellular pathways. This PRIDE project includes results from SILAC labeled and label-free replicates from the SEC-PCP-SILAC analysis of protein complexes in MCF-7 cells with inhibited and uninhibited NF-κB pathway, results from the immunoprecipitation experiment aimed at interaction partners of NF-κB factor RELA, analysis of total proteome after NF-κB inhibition, and results from SEC fractionation of untreated and unlabeled MCF-7 cells.

2024-02-28 | PXD040125 | Pride

Gene expression changes induced in the stromal cell line EL08-1D2 by co-culture with leukemic B cells (CLL)

Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-βII and the subsequent activation of NF-κB in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-β knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-βII- NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine gene expression changes induced by co-culturing with leukemic B-cells (CLL) in EL08-1D2 cells.

2013-03-08 | GSE36414 | GEO

Noncanonical pathway for regulation of CCL2 expression by an mTORC1-FOXK1 axis promotes recruitment of tumor-associated macrophages

Project description:C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)–κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that is activated in various tumor cell types. We have now identified a noncanonical pathway for regulation of CCL2 production that is mediated by mTORC1 but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1, with dephosphorylation of FOXK1 in response to mTORC1 activation resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB, and that CCL2 produced by this pathway contributes to tumor progression. Specific inhibition of FOXK1 may thus be a potential therapeutic strategy for cancer.

2017-11-30 | PXD007996 | Pride

Effect of NF-kappaB activation in bone marrow stromal cells co-cultured with CLL cells

Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-βII and the subsequent activation of NF-κB in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-β knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-βII- NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine Nemo/ IKK-gamma dependent gene expression changes in bone marrow stromal cells (BMSCs) induced by co-culturing with leukemic B-cells (CLL)

2013-03-08 | GSE36415 | GEO

Revealing the immune perturbation of black phosphorus nanomaterials to macrophages by understanding the protein corona

Project description:The increasing number of biological applications for black phosphorus (BP) nanomaterials has precipitated considerable concern about their interactions with physiological systems. Here, we demonstrate the adsorption of plasma protein onto BP nanomaterials and the subsequent immune perturbation effect on macrophages. Using liquid chromatography tandem mass spectrometry, we discovered that BP nanosheets (BPNSs) were able to bind 23.3 percent of immune proteins from plasma, while BP quantum dots (BPQDs) bound 41.8 percent of immune proteins. In particular, the protein corona dramatically reshaped BP nanomaterial-corona complexes, influenced cellular uptake, activated the NF-κB pathway and even increased cytokine secretion by 2-5-fold. BP nanomaterials induced immunotoxicity and immune perturbation in macrophages in the presence of a plasma corona. These findings offer important insights into the development of safe and effective BP nanomaterial-based therapies.

2018-05-18 | PXD009645 | Pride

TLR4-NFkB-phospho-NF-kB signaling in BMDM

Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation. The major important additions were made to TLR4 signaling description: 1) Receptor dimerization process 2) The existence of a basal nuclear NF-κB level (translocation) 3) NF-κB phosphorylation by IKK complex

2019-03-27 | MODEL1809230001 | BioModels

Targeting the NF-κB signaling pathway in Notch1-induced T cell leukemia

Project description:T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively-active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-κB target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These studies identify NF-κB as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-κB pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration

2006-12-02 | GSE6396 | GEO

Gene expression data from HEK-293T cells transfected with miR-194 mimics

Project description:Nuclear factor κB (NF-κB) pathway plays an important role in hepatocellular carcinoma (HCC) progression. miR-194 was previously shown to reduce the induction of NF-κB activity upon addition of tumor necrosis factor α (TNFα). To clarify the molecular mechanism responsible for the effect of miR-194 on NF-κB pathway, mRNA microarray assays were performed to identify the genes that were suppressed by miR-194. HEK-293T cells transfected with miR-194 mimics were cultured for RNA extraction and hybridization on Affymetrix mRNA microarrays. These were compared against the control, which were HEK-293T cells transfected with negative control mimics.

2015-07-01 | E-GEOD-70434 | biostudies-arrayexpress

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