Biology of Multiple Myeloma
Main goal of unit research is the study of the pathogenic mechanisms involved in Multiple Myeloma (MM). MM is an incurable hematological malignancy, characterized by proliferation/survival of tumor Plasma Cells (PC) inside the Bone Marrow (BM). Interactions between MM-PC and BM cellular components play a key role in MM pathogenesis, since they provide anti-apoptotic and pro- survival signals to the tumor and also confer chemo-resistance. These interactions are the main object of group studies.
In addition to conventional culture models, the group is developing, collaborating with Dr. Elisabetta Ferrero, new 3D ex-vivo culture models of MM BM microenvironment through the co-culture in bioreactor of MM-PC and BM cellular components. This system allows to model cell-cell interactions occurring in vivo, and also to predict response to drugs in individual patients.
A second project deals with Erdheim-Chester disease (ECD), a rare form of systemic non-Langerhans Histiocytosis. The disease is characterized by chronic local and systemic inflammation caused by tissue macrophages activated by an oncogenic mutation along the MAP-kinase signaling pathway, most frequently the BRAFV600E mutation. This mutation, which is shared by other cancers, including melanoma, thyroid cancer and Hairy Cell Leukemia, is effectively targeted by the specific inhibitor vemurafenib. However, vemurafenib treatment is associated with severe side effects and also with recurrences upon treatment discontinuation. Aim of unit studies is identify new therapeutic targets for ECD through the understanding of underlining pathogenic mechanisms and of the impact of drugs, particularly kinase inhibitors, also taking advantage from 3D culture of ECD tissues in bioreactor. This information may be possibly translated to other solid and haematological tumors carrying the same mutations.
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. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment. Haematologica. 2018;103(4):707-716.
Berti A, Cavalli G, Guglielmi B, Biavasco R, Campochiaro C, Tomelleri A, Nicoletti R, Panzacchi A, Ferrarini M, Dagna L. Tocilizumab in patients with multisystem Erdheim-Chester disease. Oncoimmunology. 2017;6(6):e1318237.
Ferrero E, Corti A, Haroche J, Belloni D, Colombo B, Berti A, Cavalli G, Campochiaro C, Villa A, Cohen-Aubart F, Amoura Z, Doglioni C, Dagna L, Ferrarini M. Plasma Chromogranin A as a marker of cardiovascular involvement in Erdheim-Chester disease. Oncoimmunology. 2016;5(7):e1181244.
Belloni D, Marcatti M, Ponzoni M, Ciceri F, Veschini L, Corti A, Caligaris Cappio F, Ferrarini M, Ferrero E. Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis. Exp Cell Res. 2015;330(1):1-12.
Cangi MG, Biavasco R, Cavalli G, Grassini G, Dal-Cin E, Campochiaro C, Guglielmi B, Berti A, Lampasona V, von Deimling A, Sabbadini MG, Ferrarini M, Doglioni C, Dagna L. BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease. Ann Rheum Dis. 2015;74(8):1596-602.
Diamond EL, Dagna L, Hyman DM, Cavalli G, Janku F, Estrada-Veras J, Ferrarini M, Abdel-Wahab O, Heaney ML, Scheel PJ, Feeley NK, Ferrero E, McClain KL, Vaglio A, Colby T, Arnaud L, Haroche J. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood. 2014;124(4):483-92.
Ferrarini M, Steimberg N, Ponzoni M, Belloni D, Berenzi A, Girlanda S, Caligaris-Cappio F, Mazzoleni G, Ferrero E. Ex-vivo dynamic 3-D culture of human tissues in the RCCS™ bioreactor allows the study of Multiple Myeloma biology and response to therapy. PLoS One. 2013;8(8):e71613.
Dagna L, Corti A, Langheim S, Guglielmi B, De Cobelli F, Doglioni C, Fragasso G, Sabbadini MG, Ferrarini M. Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab. J Clin Oncol. 2012;30(28):e286-90.
Belloni D, Veschini L, Foglieni C, Dell'Antonio G, Caligaris-Cappio F, Ferrarini M, Ferrero E. Bortezomib induces autophagic death in proliferating human endothelial cells. Exp Cell Res. 2010;316(6):1010-8.
Girlanda S, Fortis C, Belloni D, Ferrero E, Ticozzi P, Sciorati C, Tresoldi M, Vicari A, Spies T, Groh V, Caligaris-Cappio F, Ferrarini M. MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes. Cancer Res. 2005;65(16):7502-8.