Experimental oncology
Tumor microenvironment
Presently, the group is working on the development of novel 3D cancer culture models, aimed at reproducing fundamental features of the native microenvironment, in particular tumor-stroma mutual, dynamic interactions, that may signal tumor cells survival and confer cell adhesion mediated drug resistance (CAM-DR).
To meet the unmet need of 3D culture models in the context of cancer research, researchers have:
- introduced and validated a 3-D dynamic culture model in RCCSTM bioreactor, suitable to perform long-term culture of viable tumor samples, in particular Multiple Myeloma samples. These 3-D cultures allow to investigate the dialogue between tumor and microenvironment, to identify tumor-underlying pathogenic mechanisms and to evaluate drug response on both tumor and non-tumor components.
- reconstructed a surrogate MM microenvironment, based on the integrated use of scaffolds sequentially populated with stromal cells and MM and the rotating bioreactor, which reproduces and activates proper interactions between MM tumor and the surrounding microenvironment, that result in MM survival and resistance to bortezomib induced apoptosis.
Research activity
The group is now investigating the individual contribution of single cellular elements of the microenvironment, in particular endothelial cells, bone marrow stromal cells, either undifferentiated or differentiated toward osteoblasts and macrophages/osteoclasts to MM cells survival and drug resistance. The model may serve as a platform for a better comprehension of molecular mechanisms that regulate the interplay between tumor and its milieu, unveiling new molecular targets and can be implemented to other hematological/solid tumors.
In parallel, in collaboration with doctor Marina Ferrarini, the group investigating pathogenic mechanisms underlining the Erdheim-Chester disease, a very rare form of histiocytosis associated with the BRAFV600E mutation, aimed to identify new molecular targets. To this aim, the unit is exploiting the bioreactor technology, already demonstrated to be suitable to perform long-term cultures of viable tissue samples and to assess the impact of drugs on single cellular components.
Ferrarini M, Steimberg N, Boniotti J, Berenzi A, Belloni D, Mazzoleni G, Ferrero E. 3D-Dynamic culture models of Multiple Myeloma. Methods Mol Biol. 2017;1612:177-190.
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.
Migliavacca J, Percio S, Valsecchi R, Ferrero E, Spinelli A, Ponzoni M, Tresoldi C, Pattini L, Bernardi R, Coltella N. Hypoxia inducible factor-1α regulates a pro- invasive phenotype in acute monocytic leukemia. Oncotarget 2016 Aug 16;7(33):53540-53557.
Bianco M, Gasparri AM, Colombo B, Curnis F, Girlanda S, Ponzoni M, Bertilaccio MT, Calcinotto A, Sacchi A, Ferrero E, Ferrarini M, Chesi M, Bergsagel PL, Bellone M, Tonon G, Ciceri F, Marcatti M, Caligaris-Cappio F, Corti A. Chromogranin A is preferentially cleaved into proangiogenic peptides in the Bone Marrow of Multiple Myeloma patients. Cancer Res. 2016;76(7):1781- 91.
Valsecchi R, Coltella N, Belloni D, Ponente M, Ten Hacken E, Scielzo C, Scarfò L, Bertilaccio MT, Brambilla P, Lenti E, Martinelli Boneschi F, Brendolan A, Ferrero E, Ferrarini M, Ghia P, Tonon G, Ponzoni M, Caligaris-Cappio F, Bernardi R. HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment. Blood 2016;127(16):1987-97.
Giampietro C, Deflorian G, Gallo S, Di Matteo A, Pradella D, Bonomi S, Belloni E, Nyqvist D, Quaranta V, Confalonieri S, Bertalot G, Orsenigo F, Pisati F, Ferrero E, Biamonti G, Fredrickx E, Taveggia C, Wyatt CD, Irimia M, Di Fiore PP, Blencowe BJ, Dejana E, Ghigna C. The alternative splicing factor Nova2 regulates vascular development and lumen formation. Nat Commun. 2015 Oct 8;6:8479.
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.
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.
Ferrero E, Belloni D, Corti A, Doglioni C, Dagna L, Ferrarini M. TNF-α in Erdheim-Chester disease pericardial effusion promotes endothelial leakage in vitro and is neutralized by infliximab. Rheumatology (Oxford) 2014;53(1):198- 200.
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 RCCSTM bioreactor allows the study of Multiple Myeloma biology and response to therapy. PLoS One 2013;8(8):e71613.
