78 research outputs found

    AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression

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    Genetic investigation of crescentic glomerulonephritis (Crgn) susceptibility in the Wistar Kyoto rat, a strain uniquely susceptible to nephrotoxic nephritis (NTN), allowed us to positionally clone the activator protein-1 transcription factor Jund as a susceptibility gene associated with Crgn. To study the influence of Jund deficiency (Jund-/-) on immune-mediated renal disease, susceptibility to accelerated NTN was examined in Jund-/- mice and C57BL/6 wild-type (WT) controls. Jund-/- mice showed exacerbated glomerular crescent formation and macrophage infiltration, 10 days after NTN induction. Serum urea levels were also significantly increased in the Jund-/- mice compared with the WT controls. There was no evidence of immune response differences between Jund-/- and WT animals because the quantitative immunofluorescence for sheep and mouse IgG deposition in glomeruli was similar. Because murine Jund was inactivated by replacement with a bacterial LacZ reporter gene, we then investigated its glomerular expression by IHC and found that the Jund promoter is mainly active in Jund-/- podocytes. Furthermore, cultured glomeruli from Jund-/- mice showed relatively increased expression of vascular endothelial growth factor A (Vegfa), Cxcr4, and Cxcl12, well-known HIF target genes. Accordingly, small-interfering RNA–mediated JUND knockdown in conditionally immortalized human podocyte cell lines led to increased VEGFA and HIF1A expression. Our findings suggest that deficiency of Jund may cause increased oxidative stress in podocytes, leading to altered VEGFA expression and subsequent glomerular injury in Crgn

    AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin

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    AbstractThe Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1

    KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties

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    Mature lymphoid stromal cells (LSCs) are key organizers of immune responses within secondary lymphoid organs. Similarly, inflammation-driven tertiary lymphoid structures depend on immunofibroblasts producing lymphoid cytokines and chemokines. Recent studies have explored the origin and heterogeneity of LSC/immunofibroblasts, yet the molecular and epigenetic mechanisms involved in their commitment are still unknown. This study explored the transcriptomic and epigenetic reprogramming underlying LSC/immunofibroblast commitment. We identified the induction of lysine demethylase 6B (KDM6B) as the primary epigenetic driver of early immunofibroblast differentiation. In addition, we observed an enrichment for KDM6B gene signature in murine inflammatory fibroblasts and pathogenic stroma of patients with autoimmune diseases. Last, KDM6B was required for the acquisition of LSC/immunofibroblast functional properties, including the up-regulation of CCL2 and the resulting recruitment of monocytes. Overall, our results reveal epigenetic mechanisms that participate in the early commitment and immune properties of immunofibroblasts and support the use of epigenetic modifiers as fibroblast-targeting strategies in chronic inflammation

    KDM6B drives epigenetic reprogramming associated with lymphoid stromal cell early commitment and immune properties

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    Mature lymphoid stromal cells (LSCs) are key organizers of immune responses within secondary lymphoid organs. Similarly, inflammation-driven tertiary lymphoid structures depend on immunofibroblasts producing lymphoid cytokines and chemokines. Recent studies have explored the origin and heterogeneity of LSC/immunofibroblasts, yet the molecular and epigenetic mechanisms involved in their commitment are still unknown. This study explored the transcriptomic and epigenetic reprogramming underlying LSC/immunofibroblast commitment. We identified the induction of lysine demethylase 6B (KDM6B) as the primary epigenetic driver of early immunofibroblast differentiation. In addition, we observed an enrichment for KDM6B gene signature in murine inflammatory fibroblasts and pathogenic stroma of patients with autoimmune diseases. Last, KDM6B was required for the acquisition of LSC/immunofibroblast functional properties, including the up-regulation of CCL2 and the resulting recruitment of monocytes. Overall, our results reveal epigenetic mechanisms that participate in the early commitment and immune properties of immunofibroblasts and support the use of epigenetic modifiers as fibroblast-targeting strategies in chronic inflammation

    MSC-Regulated MicroRNAs Converge on the Transcription Factor FOXP2 and Promote Breast Cancer Metastasis

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    SummaryMesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer

    Single-cell transcriptomics reveals shared immunosuppressive landscapes of mouse and human neuroblastoma

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    BACKGROUND High-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies. METHODS We combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays. RESULTS We show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes. CONCLUSIONS Our study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment

    Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function

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    Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their interaction with immune cells. Mass spectrometry–based proteomics identified proteins transferred from CAFs to ECs, which included plasma membrane receptors. Using THY1 as an example of a transferred plasma membrane–bound protein, we showed that CAF-derived proteins increased the adhesion of a monocyte cell line to ECs. CAFs produced high amounts of matrix-bound EVs, which were the primary vehicles of protein transfer. Hence, our work paves the way for future studies that investigate how CAF-derived matrix-bound EVs influence tumor pathology by regulating the function of neighboring cancer, stromal, and immune cells

    The Oxygen Paradox, the French Paradox, and age-related diseases

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    open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

    Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway

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    Data files for the paper entitled : "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway" by Geraldine Gentric and Fatima Mechta-Grigorio
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