GelMA and Biomimetic Culture Allow the Engineering of Mineralized, Adipose and Tumor Tissue Human Microenvironments for the Study of Advanced Prostate Cancer In Vitro and In Vivo.

Increasing evidence shows bone marrow (BM)-adipocytes as a potentially important contributor in prostate cancer (PCa) bone metastases. However, a lack of relevant models has prevented to fully understand the effects of human BM-adipocytes in this microenvironment. We hypothesized that the combination of tunable gelatin methacrylamide (GelMA)-based hydrogels with the biomimetic culture of human cells would offer a versatile 3D platform to engineer human bone tumor microenvironments containing BM-adipocytes. Human osteoprogenitors, adipocytes and PCa cells were individually cultured in vitro in GelMA hydrogels, leading to mineralized, adipose and PCa tumor 3D microtissues, respectively. Osteoblast mineralization and tumor spheroid formation were tailored by hydrogel stiffness with lower stiffnesses correlating with increased mineralization and tumor spheroid size. Upon co-culture with tumor cells, BM-adipocytes underwent morphological changes and delipidation, suggesting reciprocal interactions between the cell types. When brought in vivo, the mineralized and adipose microtissues successfully formed a humanized fatty bone microenvironment, presenting, for the first time, with human adipocytes. Using this model, an increase in tumor burden was observed when human adipocytes were present, suggesting that adipocytes supported early bone tumor growth. The advanced platform presented here combines natural aspects of the microenvironment with tunable properties useful for bone tumor research. This article is protected by copyright. All rights reserved.