Tumor ENPP1(CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer [shENPP]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE193690 | GEO | 2022/01/17
REPOSITORIES: GEO
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Project description:Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF.
2022-01-17 | GSE193689 | GEO
Project description:Locoregional failure (LRF) in breast cancer patients post-surgery and post-irradiation (IR) is linked to a dismal prognosis. In a refined new model, we identified Enpp1 (Ectonucleotide pyrophosphatase /phosphodiesterase 1/CD203a) to be closely associated with LRF. Enpp1high circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of PMN-MDSC and neutrophil extracellular traps (NET) formation. Genetic and pharmacological Enpp1 inhibition or NET blockade extend relapse-free survival. Furthermore, in combination with fractionated irradiation (FD), Enpp1 abrogation obliterates LRF. Mechanistically, Enpp1-generated adenosinergic metabolites enhance Haptoglobin (Hp) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
2022-01-17 | GSE193691 | GEO
Project description:We have recently demonstrated that the ectonucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) is upregulated in the heart after myocardial infarction (MI) and initiates an aberrant metabolic cascade that worsens cell death and heart repair. Genetic loss of function approaches demonstrated that animals deficient in ENPP1 exhibited enhanced heart repair and had significantly superior post MI heart function. Whether human ENPP1 protein can be therapeutically targeted after heart injury remains unknown. Here, we engineer a humanized monoclonal antibody targeting human ENPP1 (hENPP1mAb) and demonstrate high affinity and specificity of binding to the catalytic domain of human ENPP1. In mice, genetically engineered, to express the human ENPP1 ortholog instead of murine ENPP1 (humanized ENPP1 mice), we demonstrate that administration of hENPP1mAb significantly rescued post MI heart function compared to IgG injected animals. Using metabolomics, single nuclear transcriptomics, and cellular respiration assays, we demonstrate that administration of the hENPP1mAb induces organ wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies with radiolabeled hENPP1mAb showed specific organ wide distribution without any organ toxicity. Finally, in humanized ENPP1 animals that have also been genetically engineered to exhibit antibody clearance kinetics similar to humans, we demonstrate that a single "shot" of the hENPP1mAb after MI is sufficient to rescue post infarct cardiac dysfunction. Taken together our observations provide proof of concept on how the human ectonucleotidase ENPP1 can be therapeutically targeted to prevent heart failure after MI.
2024-10-14 | GSE255826 | GEO
Project description:Through variation in the cancer cell and their immune infiltrates each tumor represents a unique problem, but therapeutic targets can be found in the shared features. Radiation therapy can change the interaction between the cancer cells and the stroma through release of innate adjuvants including the STING agonist cGAMP. Enpp1 is a phosphodiesterase that can be expressed by cancer cells and can degrade cGAMP. Enpp1 can therefore limit innate adjuvant availability following radiation therapy. We observed that many cancer cells lack Enpp1 expression, but that Enpp1 expression is retained in cells of the tumor stroma and this expression in the tumor stroma limits tumor control by radiation therapy. We demonstrate the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. We show that the mechanism requires STING and type I IFN receptor expression by non-cancer cells, and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1, and identifies a novel therapeutic Enpp1 inhibitor suitable for combination therapies in immuno-oncology.
2024-10-25 | GSE264328 | GEO
Project description:ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 which functions as a gate keeper to block cGAMP sensing in these cells. Enpp1 knockout in both cancer cells and normal tissues slowed primary tumor growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Lastly, an ENPP1 knock-in mutation that selectively abolishes ENPP1’s cGAMP hydrolysis activity phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. In summary, selectively blocking ENPP1’s cGAMP hydrolysis activity is a promising therapeutic approach for treating cancer.
2023-08-07 | GSE233659 | GEO
Project description:The goal of this study was to identify new mutations in the ENPP1 gene that produce infantile arterial calcification and fetal demise. A stillborn (proband) was diagnosed with infantile arterial calcification. Mutations in the ENPP1 gene account for ~80% of the cases of infantile arterial calcification through loss of function in both alleles (recessive inheritance).
2011-01-26 | GSE26860 | GEO
Project description:The tumor immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2D16, an oncogenic splice variant of the human epidermal growth factor receptor (HER2), has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and is associated with a poor clinical outcome in breast cancer. To understand how HER2 variants modulate the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2D16 in the mammary epithelium. We found that HER2∆16 tumors are immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ENPP1 as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of ENPP1 in aggressive HER2+ breast cancer. Knockdown of ENPP1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth that was correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent ENPP1 activation is associated with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.
2023-04-30 | GSE230179 | GEO
Project description:The tumor immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER2D16, an oncogenic splice variant of the human epidermal growth factor receptor (HER2), has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and is associated with a poor clinical outcome in breast cancer. To understand how HER2 variants modulate the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2D16 in the mammary epithelium. We found that HER2∆16 tumors are immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ENPP1 as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of ENPP1 in aggressive HER2+ breast cancer. Knockdown of ENPP1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth that was correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent ENPP1 activation is associated with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.
2023-04-30 | GSE230272 | GEO
Project description:Our microarray results showed there were up-regulated 28 genes and down-regulated 29 genes, which related depression and inflammatory response such as cytokine-cytokine receptor interaction, chemokine signaling pathway, dopaminergic synapse, glutamatergic synapse, GABAergic synapse, cholinergic synapse, and serotonergic synapse. Among these genes, especially, higher hippocampal mRNA expression of transthyretin (Ttr), Zinc finger protein of the cerebellum 1 (Zic1), and Ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2) was found in kososan-administered defeated mice than water-administered defeated mice
2021-07-13 | GSE179968 | GEO
Project description:Menisci play a vital role in load transmission, shock absorption and joint stability. The current dogma is that the menisci simply protects the cartilage and play no role in osteoarthritis (OA) unless they are injured. However, there is increasing evidence suggesting that OA menisci may not merely be bystanders in the disease process of OA. This study sought: 1) to determine the prevalence of meniscal degeneration in OA patients, 2) to examine gene expression in OA meniscal cells compared to normal control meniscal cells, and 3) to test the hypothesis that OA meniscal cells are different from normal meniscal cells. The grades of meniscal degeneration correlated in a positive fashion with the grades of articular cartilage degeneration (r = 0.672; P < 0.0001). Many genes classified in the biological processes of immune response, inflammatory response, biomineral formation and cell proliferation, including major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1), integrin, beta 2 (ITGB2), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), ankylosis, progressive homolog (ANKH) and fibroblast growth factor 7 (FGF7), were expressed at higher levels compared to normal control meniscal cells. In addition, many genes that were previously implicated in OA were also expressed at higher levels in OA meniscal cells, including ADAM metallopeptidase with thrombospondin type 1 motif, 5 (ADAMTS5). Our findings suggest that OA is a whole joint disease. Meniscal cells may play an active role in the development of OA. Investigation of the gene expression profiles of OA meniscal cells may reveal new therapeutic targets for OA therapy and also may uncover novel disease markers for early diagnosis of OA. Studies were approved by our human subjects Institutional Review Board. Menisci and articular cartilage were collected during joint replacement surgery for OA patients (OA specimens) and lower limb amputation surgery for osteosarcoma patients (normal control specimens), and graded. Meniscal cells were prepared from the meniscal tissues and expanded in monolayer culture. Differential gene expression in OA meniscal cells and normal control meniscal cells was examined using Affymetrix microarray and real time RT-PCR.
2009-11-17 | E-GEOD-19060 | biostudies-arrayexpress