WITHDRAWN: Computational modeling of multiple myeloma growth and tumor aggregate formation

Abstract

The mechanical signals received from the multiple myeloma microenvironment play a key role in bone marrow cancer development. However, the complexity of the cues received hinders the development of a novel and effective treatment. As such, agent-based computational models that consider coupled fluid and mechanical dynamics for every single cell may provide distinct perspectives and key information to adequately identify the specific tumor microenvironment. We have developed a novel 3D agent-based computational model that considers coupled fluid and particle dynamics to study multiple myeloma cell growth in response to the stimuli received from the cell microenvironment. Cell processes such as cell–cell interactions, cell maturation, and cell proliferation were considered by implementing user-defined functions in the commercial software Fluent. To calibrate and validate the developed model, we performed two experiments comparing the results of cell sedimentation velocity and cell proliferation with in vitro results. The results of the model were also compared with a finite element method model previously developed in-house. As the cells proliferated, the number of cell–cell and cell–extracellular matrix contacts increased ( ∼ 6.1% per hour), which reduced the cell maturation time ( ∼ 69.7%). Once the cells started to form aggregates, the proliferation process speeded up ( ∼ 9.9% per hour). Saturation of cell proliferation was observed after long-term simulation. Our results are qualitatively consistent with the in vitro results. In addition, they show that the cell proliferation rate increased as the number of cells considered increased. Furthermore, in a very dense aggregation, the lack of space prevented proliferation of internal cells. The model developed herein has significant advantages compared to the previous model in terms of computation, as it results in a significant reduction (84%–91%) in computational costs, thus allowing a more realistic simulation. • Agent-based model coupled with a continuous fluid model for Multiple Myeloma cell simulation. • Based on specific cell conditions, the model has been applied to study Multiple Myeloma cells’ growth and tumor aggregation formation. • Results have been validated with the literature, in-vitro experiments developed by the authors, and a previous in-house Finite Element model. • Cell maturation is stimulated by the increase in cell–cell and cell-ECM interactions, but it is inhibited by a lack of space in the inner parts of cell aggregations. • Computational costs have been reduced when compared to the previous Finite Element model.