Stromal cells regulate malignant B-cell spatial organization, survival, and drug response in a new 3D model mimicking lymphoma tumor niche

ABSTRACT Non-Hodgkin B-cell lymphomas (B-NHL) mainly develop within lymph nodes as densely packed aggregates of tumor cells and their surrounding microenvironment, creating a tumor niche specific to each lymphoma subtypes. Until now, in vitro preclinical models mimicking biomechanical forces, cellular microenvironment, and 3D organization of B lymphomas remain scarce while all these parameters constitute key determinants of lymphomagenesis and drug resistance. Using a microfluidic method based on the encapsulation of cells inside permeable, elastic, and hollow alginate microspheres, we developed a new tunable 3D-model incorporating extracellular matrix and/or stromal cells. Lymphoma B cells and stromal cells dynamically formed self-organized 3D spheroids, thus initiating a coevolution of these two cell types, reflecting their bidirectional crosstalk, and recapitulating the heterogeneity of B-NHL subtypes. In addition, this approach makes it suitable to assess in a relevant in vitro model the activity of new therapeutic agents in B-NHL.