@article{Daniela Belloni_Silvia Heltai_Maurilio Ponzoni_Antonello Villa_Barbara Vergani_Lorenza Pecciarini_Magda Marcatti_Stefania Girlanda_Giovanni Tonon_Fabio Ciceri_Federico Caligaris-Cappio_Marina Ferrarini_Elisabetta Ferrero_2018, place={Pavia, Italy}, title={Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3D surrogate microenvironment}, volume={103}, url={https://haematologica.org/article/view/8424}, DOI={10.3324/haematol.2017.167486}, abstractNote={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 myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesion-mediated 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 high-risk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated <em>in vivo</em&gt;. 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.}, number={4}, journal={Haematologica}, author={Daniela Belloni and Silvia Heltai and Maurilio Ponzoni and Antonello Villa and Barbara Vergani and Lorenza Pecciarini and Magda Marcatti and Stefania Girlanda and Giovanni Tonon and Fabio Ciceri and Federico Caligaris-Cappio and Marina Ferrarini and Elisabetta Ferrero}, year={2018}, month={Mar.}, pages={707-716} }