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The Calcineurin-NFAT-Angiopoietin 2 signaling axis in lung endothelium is critical for the establishment of lung metastases

ABSTRACT: The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE48841 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA211919

REPOSITORIES: GEO

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The Calcineurin-NFAT-Angiopoietin 2 signaling axis in lung endothelium is critical for the establishment of lung metastases

Project description:The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases. Whole lung total RNA were harvested from wildtype or Dscr-1 null mutation mice (C57BL6/J background), and subjected to Affymetrix Mouse 430 2.0 array in duplicate conditions. Alternatively, primary cultured human lung endothelial cells (LONZA) were transfected with either siRNA, control or DSCR-1, or adenovirus expressing DSCR-1 or mock control. Adenovirally transfected lung endothelial cells were serum-starved (EBM-2 (LONZA) plus 0.5% FBS) and treated with 50ng/ml VEGF for indicated time points. After the treatments, total RNA was harvested and subjected to Affymetrix Human U133 Plus 2.0 array.

2015-01-01 | E-GEOD-48841 | biostudies-arrayexpress

Loss of Down syndrome critical region-1 leads to cholesterol metabolic dysfunction that exaggerates hypercholesterolemia in ApoE-null background

Project description:Down syndrome critical region (DSCR)-1functions as a feedback modulator for calcineurin- nuclear factor for activated T cell(NFAT) signals, which are crucial for cell proliferation and inflammation. Stable expression of DSCR-1 inhibits pathological angiogenesis and septic inflammation. DSCR-1 also plays a critical role in vascular wall remodeling associated with aneurysm development that occurs primarily in smooth muscle cells. Besides, Dscr-1 deficiency promotes the M1-to M2-like phenotypic switch in macrophages, which correlates to the reduction of denatured cholesterol uptakes. However, the distinct roles of DSCR-1 in cholesterol and lipid metabolism are not well understood. Here, we show that loss of apolipoprotein (Apo) E in mice with chronic hypercholesterolemia induced Dscr-1expression in the liver and aortic atheroma. InDscr-1-null mice fed a high-fat diet, oxidative- and endoplasmic reticulum (ER)-stress was induced and sterol regulatory element-binding protein (SREBP) 2production in hepatocytes was stimulated. This exaggerated ApoE-/--mediated nonalcoholic fatty liver disease (NAFLD) and subsequent hypercholesterolemia. Genome wide screening revealed that loss of both ApoE and Dscr-1 resulted in the induction of immune- and leukocyte activation-related genes in the liver compared to ApoE deficiency alone. However, expression of inflammation-activated markers and levels of monocyte adhesion were suspended upon induction of the Dscr-1 null background in the aortic endothelium. Collectively, our study shows that the combined loss of Dscr-1 and ApoE causes metabolic dysfunction in the liver but reduces atherosclerotic plaques, thereby leading to a dramatic increase in serum cholesterol and the formation of sporadic vasculopathy.

2021-04-19 | GSE172283 | GEO

The Calcineurin-NFAT-Angiopoietin 2 signaling axis in lung endothelium is critical for the establishment of lung metastases

Project description:The Calcineurin-NFAT-Angiopoietin 2 signaling axis in lung endothelium is critical for the establishment of lung metastases

| PRJNA211919 | ENA

Tumor exosome integrins determine organotropic metastasis

Project description:Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes

2015-06-17 | E-GEOD-68919 | biostudies-arrayexpress

Identification of differential expressed genes among reprogrammed cells cultured under control condition and calcineurin-NFAT pathway inhibition condition at reprogramming day 3 and day 6 through genome-wide transcript profiling

Project description:Inhibition of calcineurin-NFAT pathway at the early stage can block somatic cell reprogramming. In order to study how the calcineurin-NFAT pathway contributes to the early stage of reprogramming, we designed this microarray experiment and tried to find out which genes or signalings were changed after inhibition of calcineurin-NFAT signaling by CSA (a specific inhibitor of calcineurin-NFAT pathway).

2015-12-01 | GSE67739 | GEO

Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer

Project description:This experiment looks at the dissection of the microenvironment in the lung metastatic niche in a model of murine triple-negative breast cancer as disease progresses. Mice received an orthotopic inoculation of 4T1 cells and disease was allowed to progress for 7, 14, or 21 days correlating to the pre-metastatic, micro-metastatic, and metastatic niche, respectively. Healthy controls were obtained along with each time point.

2023-03-06 | E-MTAB-11741 | biostudies-arrayexpress

Calcineurin/NFAT signaling inhibits myeloid hematopoiesis in mice.

Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates

2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress

Granulocyte-monocyte progenitor cell cycle regulation occurs through calcium flux and calcineurin-NFAT signaling via Flt3-L

Project description:Complex regulatory mechanisms control continuous maintenance of myeloid progenitors and renewal of differentiated cells. Transcription factors play a important role in these processes. Here we report that the activation the calcineurin-NFAT signaling pathway inhibit the proliferation of myeloid granulocyte-monocyte progenitor (GMP). Myeloid progenitor subtypes possessed different susceptibilities to Ca2+ flux induction and consequently differential engagement of the calcineurin-NFAT pathway. This study show that inhibition of the calcineurin-NFAT pathway enhanced proliferation of GMPs both in vivo and in vitro. The calcineurin-NFAT signaling in GMPs is initiated through Flt3-L. The inhibition of the calcineurin-NFAT pathway altered the expression of the cell cycle regulation genes CDK4, CDK6, and CDKN1A, thus enabling faster cell cycle progression. The extensive use of NFAT inhibitors in the clinic should take into account that, in addition to the immunosuppression role in lymphoid cells, these NFAT inhibitors also affect the maintenance of the myeloid compartment. Microarray technology was used to understand the effects of NFAT inhibitors on C-kit enriched lineage negative cells.

2014-12-31 | GSE47208 | GEO

Tumor exosome integrins determine organotropic metastasis

2015-06-17 | GSE68919 | GEO

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis by a NGFR-dependent mechanism

Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in establishing the lymph node pre-metastatic niche by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and are taken up by lymphatic endothelial cells reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. Analysis of involved factors demonstrated that the neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended mice survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support that NGFR is secreted in sEVs favoring lymph node pre-metastatic niche formation and lymph node metastasis in melanoma.

2021-07-16 | PXD024108 | Pride

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