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1. In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-κB activation observed in vivo

Author

Colombo, Federica, Guzzeloni, Virginia, Kizilirmak, Cise, Brambilla, Francesca, Garcia-Manteiga, Jose Manuel, Tascini, Anna Sofia, Moalli, Federica, Mercalli, Francesca, Ponzoni, Maurilio, Mezzapelle, Rosanna, Ferrarini, Marina, Ferrero, Elisabetta, Visone, Roberta, Rasponi, Marco, Bianchi, Marco E., Zambrano, Samuel, and Agresti, Alessandra

Published
2024
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3. miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

Author

Vergani, Elisabetta, Dugo, Matteo, Cossa, Mara, Frigerio, Simona, Di Guardo, Lorenza, Gallino, Gianfrancesco, Mattavelli, Ilaria, Vergani, Barbara, Lalli, Luca, Tamborini, Elena, Valeri, Barbara, Gargiuli, Chiara, Shahaj, Eriomina, Ferrarini, Marina, Ferrero, Elisabetta, Gomez Lira, Macarena, Huber, Veronica, Del Vecchio, Michele, Sensi, Marialuisa, Leone, Biagio Eugenio, Santinami, Mario, Rivoltini, Licia, Rodolfo, Monica, and Vallacchi, Viviana

Published
2020
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4. Supplementary Figure Legends from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, primary, Colombo, Barbara, primary, Curnis, Flavio, primary, Girlanda, Stefania, primary, Ponzoni, Maurilio, primary, Bertilaccio, Maria Teresa Sabrina, primary, Calcinotto, Arianna, primary, Sacchi, Angelina, primary, Ferrero, Elisabetta, primary, Ferrarini, Marina, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Bellone, Matteo, primary, Tonon, Giovanni, primary, Ciceri, Fabio, primary, Marcatti, Magda, primary, Caligaris-Cappio, Federico, primary, and Corti, Angelo, primary

Published
2023
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5. Data from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, primary, Colombo, Barbara, primary, Curnis, Flavio, primary, Girlanda, Stefania, primary, Ponzoni, Maurilio, primary, Bertilaccio, Maria Teresa Sabrina, primary, Calcinotto, Arianna, primary, Sacchi, Angelina, primary, Ferrero, Elisabetta, primary, Ferrarini, Marina, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Bellone, Matteo, primary, Tonon, Giovanni, primary, Ciceri, Fabio, primary, Marcatti, Magda, primary, Caligaris-Cappio, Federico, primary, and Corti, Angelo, primary

Published
2023
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6. Supplementary Figures S1-S5 from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, primary, Colombo, Barbara, primary, Curnis, Flavio, primary, Girlanda, Stefania, primary, Ponzoni, Maurilio, primary, Bertilaccio, Maria Teresa Sabrina, primary, Calcinotto, Arianna, primary, Sacchi, Angelina, primary, Ferrero, Elisabetta, primary, Ferrarini, Marina, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Bellone, Matteo, primary, Tonon, Giovanni, primary, Ciceri, Fabio, primary, Marcatti, Magda, primary, Caligaris-Cappio, Federico, primary, and Corti, Angelo, primary

Published
2023
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7. Supplementary Tables S1-S4 from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, primary, Colombo, Barbara, primary, Curnis, Flavio, primary, Girlanda, Stefania, primary, Ponzoni, Maurilio, primary, Bertilaccio, Maria Teresa Sabrina, primary, Calcinotto, Arianna, primary, Sacchi, Angelina, primary, Ferrero, Elisabetta, primary, Ferrarini, Marina, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Bellone, Matteo, primary, Tonon, Giovanni, primary, Ciceri, Fabio, primary, Marcatti, Magda, primary, Caligaris-Cappio, Federico, primary, and Corti, Angelo, primary

Published
2023
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8. Supplementary Methods from Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, primary, Colombo, Barbara, primary, Curnis, Flavio, primary, Girlanda, Stefania, primary, Ponzoni, Maurilio, primary, Bertilaccio, Maria Teresa Sabrina, primary, Calcinotto, Arianna, primary, Sacchi, Angelina, primary, Ferrero, Elisabetta, primary, Ferrarini, Marina, primary, Chesi, Marta, primary, Bergsagel, P. Leif, primary, Bellone, Matteo, primary, Tonon, Giovanni, primary, Ciceri, Fabio, primary, Marcatti, Magda, primary, Caligaris-Cappio, Federico, primary, and Corti, Angelo, primary

Published
2023
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9. Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production

Author

Cantoni, Eleonora, primary, Merelli, Ivan, additional, Stefanoni, Davide, additional, Tomelleri, Alessandro, additional, Campochiaro, Corrado, additional, Giordano, Vito, additional, Panigada, Maddalena, additional, Baldissera, Elena M, additional, Merlo Pich, Laura, additional, Natoli, Valentina, additional, Ziogas, Athanasios, additional, Domínguez-Andrés, Jorge, additional, De Luca, Giacomo, additional, Mazza, Davide, additional, Zambrano, Samuel, additional, Gnani, Daniela, additional, Ferrarini, Marina, additional, Ferrero, Elisabetta, additional, Agresti, Alessandra, additional, Vergani, Barbara, additional, Leone, Biagio Eugenio, additional, Cenci, Simone, additional, Ravelli, Angelo, additional, Matucci-Cerinic, Marco, additional, D’Alessandro, Angelo, additional, Joosten, Leo A B, additional, Dagna, Lorenzo, additional, Netea, Mihai G, additional, Molteni, Raffaella, additional, and Cavalli, Giulio, additional

Published
2023
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10. Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production

Author

Cantoni, E, Merelli, I, Stefanoni, D, Tomelleri, A, Campochiaro, C, Giordano, V, Panigada, M, Baldissera, E, Merlo Pich, L, Natoli, V, Ziogas, A, Domínguez-Andrés, J, De Luca, G, Mazza, D, Zambrano, S, Gnani, D, Ferrarini, M, Ferrero, E, Agresti, A, Vergani, B, Leone, B, Cenci, S, Ravelli, A, Matucci-Cerinic, M, D'Alessandro, A, Joosten, L, Dagna, L, Netea, M, Molteni, R, Cavalli, G, Cantoni, Eleonora, Merelli, Ivan, Stefanoni, Davide, Tomelleri, Alessandro, Campochiaro, Corrado, Giordano, Vito, Panigada, Maddalena, Baldissera, Elena M, Merlo Pich, Laura, Natoli, Valentina, Ziogas, Athanasios, Domínguez-Andrés, Jorge, De Luca, Giacomo, Mazza, Davide, Zambrano, Samuel, Gnani, Daniela, Ferrarini, Marina, Ferrero, Elisabetta, Agresti, Alessandra, Vergani, Barbara, Leone, Biagio Eugenio, Cenci, Simone, Ravelli, Angelo, Matucci-Cerinic, Marco, D'Alessandro, Angelo, Joosten, Leo A B, Dagna, Lorenzo, Netea, Mihai G, Molteni, Raffaella, Cavalli, Giulio, Cantoni, E, Merelli, I, Stefanoni, D, Tomelleri, A, Campochiaro, C, Giordano, V, Panigada, M, Baldissera, E, Merlo Pich, L, Natoli, V, Ziogas, A, Domínguez-Andrés, J, De Luca, G, Mazza, D, Zambrano, S, Gnani, D, Ferrarini, M, Ferrero, E, Agresti, A, Vergani, B, Leone, B, Cenci, S, Ravelli, A, Matucci-Cerinic, M, D'Alessandro, A, Joosten, L, Dagna, L, Netea, M, Molteni, R, Cavalli, G, Cantoni, Eleonora, Merelli, Ivan, Stefanoni, Davide, Tomelleri, Alessandro, Campochiaro, Corrado, Giordano, Vito, Panigada, Maddalena, Baldissera, Elena M, Merlo Pich, Laura, Natoli, Valentina, Ziogas, Athanasios, Domínguez-Andrés, Jorge, De Luca, Giacomo, Mazza, Davide, Zambrano, Samuel, Gnani, Daniela, Ferrarini, Marina, Ferrero, Elisabetta, Agresti, Alessandra, Vergani, Barbara, Leone, Biagio Eugenio, Cenci, Simone, Ravelli, Angelo, Matucci-Cerinic, Marco, D'Alessandro, Angelo, Joosten, Leo A B, Dagna, Lorenzo, Netea, Mihai G, Molteni, Raffaella, and Cavalli, Giulio

Abstract

Objective: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

Published
2023

11. HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

Author

Valsecchi, Roberta, Coltella, Nadia, Belloni, Daniela, Ponente, Manfredi, ten Hacken, Elisa, Scielzo, Cristina, Scarfò, Lydia, Bertilaccio, Maria Teresa Sabrina, Brambilla, Paola, Lenti, Elisa, Martinelli Boneschi, Filippo, Brendolan, Andrea, Ferrero, Elisabetta, Ferrarini, Marina, Ghia, Paolo, Tonon, Giovanni, Ponzoni, Maurilio, Caligaris-Cappio, Federico, and Bernardi, Rosa

Published
2016
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14. 3D-Dynamic Culture Models of Multiple Myeloma

Author

Ferrarini, Marina, primary, Steimberg, Nathalie, additional, Boniotti, Jennifer, additional, Berenzi, Angiola, additional, Belloni, Daniela, additional, Mazzoleni, Giovanna, additional, and Ferrero, Elisabetta, additional

Published
2017
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16. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis

Author

Ferrero, Elisabetta, primary, Villa, Antonello, additional, Stefanoni, Davide, additional, Nemkov, Travis, additional, D’Alessandro, Angelo, additional, Tengesdal, Isak, additional, Belloni, Daniela, additional, Molteni, Raffaella, additional, Vergani, Barbara, additional, De Luca, Giacomo, additional, Grassini, Greta, additional, Cangi, Maria Giulia, additional, Dagna, Lorenzo, additional, Doglioni, Claudio, additional, Cavalli, Giulio, additional, and Ferrarini, Marina, additional

Published
2021
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19. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease

Author

Biavasco, Riccardo, primary, Molteni, Raffaella, additional, Stefanoni, Davide, additional, Nemkov, Travis, additional, Netea, Mihai G., additional, Domínguez-Andrés, Jorge, additional, Arts, Rob JW, additional, Merelli, Ivan, additional, Mazza, Davide, additional, Zambrano, Samuel, additional, Panigada, Maddalena, additional, Cantoni, Eleonora, additional, Tengesdal, Isak, additional, Maksud, Philippe, additional, Piras, Francesco, additional, De Luca, Giacomo, additional, Cassina, Laura, additional, Distefano, Gianfranco, additional, Loffreda, Alessia, additional, Gnani, Daniela, additional, Doglioni, Claudio, additional, Tomelleri, Alessandro, additional, Campochiaro, Corrado, additional, Joosten, Leo, additional, Dinarello, Charles A, additional, Kajaste-Rudnitski, Anna, additional, Haroche, Julien, additional, Cardaci, Simone, additional, Cenci, Simone, additional, Dagna, Lorenzo, additional, Ferrarini, Marina, additional, Ferrero, Elisabetta, additional, Boletta, Alessandra, additional, D'Alessandro, Angelo, additional, Montini, Eugenio, additional, and Cavalli, Giulio, additional

Published
2021
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23. Additional file 3 of miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

Author

Vergani, Elisabetta, Dugo, Matteo, Cossa, Mara, Frigerio, Simona, Di Guardo, Lorenza, Gallino, Gianfrancesco, Mattavelli, Ilaria, Vergani, Barbara, Lalli, Luca, Tamborini, Elena, Valeri, Barbara, Gargiuli, Chiara, Shahaj, Eriomina, Ferrarini, Marina, Ferrero, Elisabetta, Gomez Lira, Macarena, Huber, Veronica, Del Vecchio, Michele, Sensi, Marialuisa, Leone, Biagio Eugenio, Santinami, Mario, Rivoltini, Licia, Rodolfo, Monica, and Vallacchi, Viviana

Abstract

Additional file 2: Supplementary Fig. S1. Altered miR-146a expression influences BRAF/MEKi sensitivity and apoptosis in melanoma. A) Boxplots representing IC50 values of 6 matched PLX4032-resistant (R) and sensitive (S) melanoma cell lines to PLX4032 (vemurafenib), BRAFi (dabrafenib), MEKi (trametinib), to the combined treatment BRAF/MEKi, and to sTRAIL-induced apoptosis. B) Inverse correlation between miR-146a expression levels and IC50 values of PLX4032, BRAFi and MEKi in melanoma cell lines (Spearman analysis). C) Forced expression of miR-146a (+m-miR-146a) in LM16R cell line and in LM69 and LM70 short term cultures increased the effects of PLX4032 treatment as shown by reduced cell growth and increased cell cytotoxicity and apoptosis, evaluated by CCK8, LDH and caspase 8 and 3/7 activity. D) Inhibition of miR-146a expression (i-miR-146a) in LM16 cells increased cell proliferation and decreased the release of LDH and the apoptosis rate as evaluated by CCK8, LDH and caspase 3/7 activity. E) Overexpression of miR-146a (m-miR-146a) upon PLX4032, BRAF/MEKi and sTRAIL treatments in LM47R cells increased cell cytotoxicity and apoptosis, as evaluated by LDH and caspase 8 and 3/7 activity. Data are plotted compared to scrambled control. *: p < 0.05, **: p < 0.01, ***: p < 0.0001 by Student’s unpaired t test. Supplementary Fig. S2. COX2 inhibition increases sensitivity to PLX4032 and to BRAF/MEKi and reduces PGE2 release. A) Relative luciferase activity after co-transfection of PTGS2 3’UTR luciferase reporter vector or control vector with miR-146a mimic or mimic negative control. Experiment was performed in LM16R cells. B) Inverse correlation between miR-146a expression levels and IC50 values of PLX4032 in melanoma cell lines (Spearman analysis). C) Western blot analyses showing downregulation of COX2 after transfection with siRNA against COX2 (siCOX2) compared to scrambled control (S). COX2 protein levels were downregulated to 15%, as determined by quantification of the signal and expressed as the ratio of COX2/Actin intensity. Experiment was performed with LM47R cells. D) Silencing of COX2 by siRNA transfection enhanced cell growth inhibition and increased cell cytotoxicity and apoptosis upon treatment with PLX4032 compared to scrambled control. E) PGE2 release in culture supernatants following 24 h treatment with the COX2 inhibitors celecoxib and NS398, alone or in combination with BRAF/MEKi. F) Combined treatment with celecoxib increased cell growth inhibition and cytotoxicity by PLX4032. ●: interaction index = 1. G) Dose-dependent effect of celecoxib alone (5, 10, 20, 40, 50 and 80 μM) and combined with PLX4032 (3 μM) on cell growth. ●: interaction index = 1 at the dose of 50 μM of celecoxib combined with PLX4032. P values were calculated by Student’s unpaired t test in A, D and F, by one-way ANOVA followed by Bonferroni correction in E, and by two-way ANOVA followed by Bonferroni correction in G. *: p < 0.05, **: p < 0.01, ***: p < 0.0001. Supplementary Fig. S3. miR-146a expression levels are inversely correlated with levels of target genes. Analysis of correlation between miR-146a expression and its target genes EGFR, CCL2 and BCL2L1 in metastatic melanoma specimens. The rp and p values resulting from Pearson analysis are shown. Supplementary Fig. S4. Dynamic culture in bioreactor preserves TME architecture of 3D tumor explants. Representative histological images of H&E-stained 3D tumor sections after 3 days culture in bioreactor. The marked areas in the left panels are shown at higher magnification in the right panels to display the preserved cellularity and tumor tissue histo-architecture. Scale bar 80 μM. Supplementary Fig. S5. miR-146a overexpression increases drug sensitivity in 3D cultures of tumor explants. A) Modulation of direct and indirect miR-146a target genes upon transfection of miR-146a mimic (m-miR-146a) compared to scrambled-transfected control (S) in 3D cultures of BRAF-mutated melanoma tumors from naïve patients. AU: arbitrary units. B) Decreased staining for Ki67 and pERK proliferating cells and increased Caspase 3 positive cells in 3D cultures upon treatment with BRAF/MEKi and transfection with miR-146a (m-miR-146a) or scrambled control (S). Scale bar 10 um.

Published
2020
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25. A relapsing inflammatory syndrome and active human herpesvirus 8 infection

Author

Danga, Lorenzo, Broccolo, Francesco, Paties, Carlo T., Ferrarini, Marina, Sarmati, Loredana, Praderio, Luisa, Sabbadini, Maria Grazia, Lusso, Paolo, and Malnati, Mauro S.

Subjects
Human herpesvirus 8 -- Health aspects, Herpes -- Case studies, Herpesvirus diseases -- Case studies, Diseases -- Relapse
Abstract

A description about an immunocompetent 61-year old woman who was negative for human immunodeficiency virus and who had recurrent human herpesvirus 8 (HHV-8) infection associated with a relapsing systematic inflammatory syndrome characterized by fever, lymphadenopathy, splenomegaly, edema and rash is presented. The HHV-8 infection, also known as Kaposi's sarcoma (KS)- associated herpesvirus developed 10 months after the initial clinical presentation.

Published
2005

26. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma

Author

Clementi, Rita, Sabbadini, Maria Grazia, Danesino, Cesare, Dagna, Lorenzo, Rugarli, Claudio, Ferrarini, Marina, Dianzani, Umberto, Ciceri, Fabio, Bregni, Marco, Dupre, Loic, Maccario, Rita, Chiocchetti, Annalisa, and Locatelli, Franco

Subjects
Gene mutations -- Evaluation, Lymphoproliferative disorders -- Case studies, Lymphoproliferative disorders -- Genetic aspects
Abstract

A 27-year old man with the autoimmune lymphoproliferative syndrome and a large-B-cell lymphoma had heterozygous mutations in the Fas and perforin (Prf1) genes where the Fas mutation was inherited from his healthy father and the Prf1 mutation from his healthy mother. The combined effect of the two mutant genes may have contributed to the development of the autoimmune lymphoproliferative syndrome and lymphoma in this patient.

Published
2004

27. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis.

Author

Ferrero, Elisabetta, Villa, Antonello, Stefanoni, Davide, Nemkov, Travis, D'Alessandro, Angelo, Tengesdal, Isak, Belloni, Daniela, Molteni, Raffaella, Vergani, Barbara, Luca, Giacomo De, Grassini, Greta, Cangi, Maria Giulia, Dagna, Lorenzo, Doglioni, Claudio, Cavalli, Giulio, and Ferrarini, Marina

Subjects
CYTOKINES, GENETIC mutation, SKIN, PROTEIN kinase inhibitors, IMMUNOHISTOCHEMISTRY, MACROPHAGES, LANGERHANS-cell histiocytosis, GENE expression, CELLULAR signal transduction, CYTOKINE release syndrome, PHOSPHORYLATION
Abstract

The article presents a case study which characterized the functional and metabolic outcomes of an activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation in a patient affected by Langerhans-related histiocytosis. Topics include case of a patient with articular, pituitary and skin involvement, comparison between the supernatant of tissue lesions and tissue culture medium, and clinical effectiveness MAPK pathway inhibition with selective MEK inhibitors in histiocytosis patients.

Published
2022
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37. 3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target

Author

Villa, Antonello, primary, Belloni, Daniela, additional, Vergani, Barbara, additional, Cenci, Simone, additional, Cavalli, Giulio, additional, Biavasco, Riccardo, additional, Rodolfo, Monica, additional, Cangi, Maria Giulia, additional, Doglioni, Claudio, additional, Dagna, Lorenzo, additional, Ferrero, Elisabetta, additional, and Ferrarini, Marina, additional

Published
2018
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39. Killing of laminin receptor-positive human lung cancers by tumor-infiltrating lymphocytes bearing gamma-delta+ T-cell receptors

Author

Ferrarini, Marina, Heltai, Silvia, Pupa, Serenella M., Menard, Sylvie, and Zocchi, M. Raffaella

Subjects
T cells -- Receptors, Lung cancer, Tumor-infiltrating lymphocytes -- Health aspects, Health
Abstract

Background. The monomeric laminin receptor, a 67-kd high-affinity laminin-binding protein, is expressed by a variety of normal cell types. Overexpression and abnormal surface distribution of this receptor have been demonstrated in tumor cells, where it appears to promote tumor invasion and metastasis. Previously, we reported the existence of an association between laminin receptor overexpression by lung c-ancer cells and the presence of tumor-infiltrating lymphocytes (TILs) bearing [gamma][zeta] T-cell receptors. [gamma][zeta]+ lymphocytes represent a sizable fraction of the TILs in approximately one fourth of lung cancers analyzed thus far. Purpose: The aim of this study was to determine whether [gamma][zeta]+ TILs might participate in the immune response against lung cancer through recognition of monomeric laminin receptors expressed by tumor cells. Methods: Tumor cells from 11 lung cancer specimens exhibiting sizable [gamma][zeta]+ T-cell infiltrates and from 11 other specimens infiltrated predominantly by lymphocytes bearing [alpha][beta] T-cell receptors were analyzed for expression of the monomeric laminin receptor by use of the monoclonal antibody (MAb) MLuC5. [gamma][zeta]+ TILs and [alpha][beta]+ TILs derived from four tumors were each examined for cytotoxic activity toward lung cancer target cells by use of a standard 51Cr-release assay and lung tumor cell lines expressing different levels of surface monomeric laminin receptor. The ability of MAbs directed against the laminin receptor (i.e., MLUC5) or against [gamma][zeta] T-cell receptors (i.e., Ti[gamma]A and A13) as well as laminin peptides known to bind to the laminin receptor to inhibit TIL-mediated target cell lysis was also determined. Results: We confirmed that the association between overexpression of the monomeric laminin receptor by lung tumor cells and the presence of [gamma][zeta]+ TILs is statistically significant (two-sided P = .003; Fisher's exact test). We also observed a relationship between the levels of laminin receptor expression on cultured lung cancer cells and their susceptibility to specific lysis by [gamma][zeta]+, but not [alpha][beta]+, TILs. This specific cell killing was not T-cell receptor mediated, but it was inhibited by addition of the anti-monomeric laminin receptor MAb MLUC5 and by a synthetic peptide corresponding to amino acids 2091-2108 of the laminin A chain. Conclusions and Implications: Our results indicate that [gamma][zeta]+ TILs localized at human lung cancer sites can kill tumor cells in a process that involves interaction with the monomeric laminin receptor. The infiltration of [gamma][zeta]+ TILs at lung tumor sites may represent a first line of defense against cells undergoing malignant transformation. [J Natl Cancer Inst 1996;88:436-411

Published
1996

40. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3d surrogate microenvironment

Author

Belloni, D, Heltai, S, Ponzoni, M, Villa, A, Vergani, B, Pecciarini, L, Marcatti, M, Girlanda, S, Tonon, G, Ciceri, F, Caligaris-Cappio, F, Ferrarini, M, Ferrero, E, Belloni, Daniela, Heltai, Silvia, Ponzoni, Maurilio, Villa, Antonello, Vergani, Barbara, Pecciarini, Lorenza, Marcatti, Magda, Girlanda, Stefania, Tonon, Giovanni, Ciceri, Fabio, Caligaris-Cappio, Federico, Ferrarini, Marina, Ferrero, Elisabetta, Belloni, D, Heltai, S, Ponzoni, M, Villa, A, Vergani, B, Pecciarini, L, Marcatti, M, Girlanda, S, Tonon, G, Ciceri, F, Caligaris-Cappio, F, Ferrarini, M, Ferrero, E, Belloni, Daniela, Heltai, Silvia, Ponzoni, Maurilio, Villa, Antonello, Vergani, Barbara, Pecciarini, Lorenza, Marcatti, Magda, Girlanda, Stefania, Tonon, Giovanni, Ciceri, Fabio, Caligaris-Cappio, Federico, Ferrarini, Marina, and Ferrero, Elisabetta

Abstract

Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myelomabone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electronmicroscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesionmediated drug resistance were significantly higher in 3D than in 2D parallel co-cultures. The contribution of the VLA-4/VCAM1 pathway to resistance to bortezomib was modeled by the use of VCAM1 transfectants. Soluble factor-mediated drug resistance could be also demonstrated in both 2D and 3D co-cultures. The system was then successfully applied to co-cultures of primary myeloma cells-primary myeloma bone marrow stromal cells from patients and endothelial cells, allowing the development of functional myeloma-stroma interactions and MM cell long-term survival. Significantly, genomic analysis performed in a highrisk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated in vivo. Finally, the impact of bortezomib on myeloma cells and on specialized functions of the microenvironment could be evaluated. Our findings indicate that 3D dynamic culture of reconstructed human multiple myeloma microenvironments in bioreactor may represent a useful platform for drug testing and for studying tumor-stroma molecular interactions.

Published
2018

41. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease

Author

Molteni, Raffaella, Biavasco, Riccardo, Stefanoni, Davide, Nemkov, Travis, Domínguez-Andrés, Jorge, Arts, Rob J., Merelli, Ivan, Mazza, Davide, Zambrano, Samuel, Panigada, Maddalena, Cantoni, Eleonora, Tengesdal, Isak W., Maksud, Philippe, Piras, Francesco, Cesana, Daniela, Cassina, Laura, Distefano, Gianfranco, Loffreda, Alessia, Gnani, Daniela, De Luca, Giacomo, Tomelleri, Alessandro, Campochiaro, Corrado, Joosten, Leo A.B., Dinarello, Charles A., Kajaste-Rudnitski, Anna, Haroche, Julien, Cardaci, Simone, Cenci, Simone, Dagna, Lorenzo, Doglioni, Claudio, Ferrarini, Marina, Ferrero, Elisabetta, Boletta, Alessandra, D'Alessandro, Angelo, Montini, Eugenio, Netea, Mihai G., and Cavalli, Giulio

Abstract

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Published
2021
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43. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment

Author

Belloni, Daniela, primary, Heltai, Silvia, additional, Ponzoni, Maurilio, additional, Villa, Antonello, additional, Vergani, Barbara, additional, Pecciarini, Lorenza, additional, Marcatti, Magda, additional, Girlanda, Stefania, additional, Tonon, Giovanni, additional, Ciceri, Fabio, additional, Caligaris-Cappio, Federico, additional, Ferrarini, Marina, additional, and Ferrero, Elisabetta, additional

Published
2018
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44. Tocilizumab in patients with multisystem Erdheim–Chester disease

Author

Berti, Alvise, primary, Cavalli, Giulio, additional, Guglielmi, Barbara, additional, Biavasco, Riccardo, additional, Campochiaro, Corrado, additional, Tomelleri, Alessandro, additional, Nicoletti, Roberto, additional, Panzacchi, Andrea, additional, Ferrarini, Marina, additional, and Dagna, Lorenzo, additional

Published
2017
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45. Plasma Chromogranin A as a marker of cardiovascular involvement in Erdheim–Chester disease

Author

Ferrero, Elisabetta, primary, Corti, Angelo, additional, Haroche, Julien, additional, Belloni, Daniela, additional, Colombo, Barbara, additional, Berti, Alvise, additional, Cavalli, Giulio, additional, Campochiaro, Corrado, additional, Villa, Antonello, additional, Cohen-Aubart, Fleur, additional, Amoura, Zahir, additional, Doglioni, Claudio, additional, Dagna, Lorenzo, additional, and Ferrarini, Marina, additional

Published
2016
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46. Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients

Author

Bianco, Mimma, primary, Gasparri, Anna Maria, additional, Colombo, Barbara, additional, Curnis, Flavio, additional, Girlanda, Stefania, additional, Ponzoni, Maurilio, additional, Bertilaccio, Maria Teresa Sabrina, additional, Calcinotto, Arianna, additional, Sacchi, Angelina, additional, Ferrero, Elisabetta, additional, Ferrarini, Marina, additional, Chesi, Marta, additional, Bergsagel, P. Leif, additional, Bellone, Matteo, additional, Tonon, Giovanni, additional, Ciceri, Fabio, additional, Marcatti, Magda, additional, Caligaris-Cappio, Federico, additional, and Corti, Angelo, additional

Published
2016
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50. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Author

Diamond, Eli L., primary, Dagna, Lorenzo, additional, Hyman, David M., additional, Cavalli, Giulio, additional, Janku, Filip, additional, Estrada-Veras, Juvianee, additional, Ferrarini, Marina, additional, Abdel-Wahab, Omar, additional, Heaney, Mark L., additional, Scheel, Paul J., additional, Feeley, Nancy K., additional, Ferrero, Elisabetta, additional, McClain, Kenneth L., additional, Vaglio, Augusto, additional, Colby, Thomas, additional, Arnaud, Laurent, additional, and Haroche, Julien, additional

Published
2014
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