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

• Published in: Advanced healthcare materials 2023-06, Vol.12 (14), p.e2201701-n/a
• Main Authors: Bessot, Agathe, Gunter, Jennifer, Waugh, David, Clements, Judith A., Hutmacher, Dietmar W., McGovern, Jacqui, Bock, Nathalie
• Format: Article
• Language: English
• Subjects: 3D cancer models; Adipocytes; Biomimetics; Bone cancer; Bone growth; Bone marrow; Bone Neoplasms - pathology; bone tumor microenvironments; Bone tumors; Cell culture; Gelatin; Gelatin - pharmacology; GelMA; humanized models; Humans; Hydrogels; Hydrogels - pharmacology; In vivo methods and tests; Male; Metastases; Methacrylamide; microtissues; Mineralization; Prostate cancer; Prostatic Neoplasms - pathology; Stiffness; Tissue Engineering; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 2192-2640; 2192-2659; 2192-2659
• DOI: 10.1002/adhm.202201701

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 the full understanding of the effects of human BM‐adipocytes in this microenvironment. It is 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 are individually cultured in vitro in GelMA hydrogels, leading to mineralized, adipose, and PCa tumor 3D microtissues, respectively. Osteoblast mineralization and tumor spheroid formation are tailored by hydrogel stiffness with lower stiffnesses correlating with increased mineralization and tumor spheroid size. Upon coculture with tumor cells, BM‐adipocytes undergo morphological changes and delipidation, suggesting reciprocal interactions between the cell types. When brought in vivo, the mineralized and adipose microtissues successfully form a humanized fatty bone microenvironment, presenting, for the first time, with human adipocytes. Using this model, an increase in tumor burden is observed when human adipocytes are present, suggesting that adipocytes support early bone tumor growth. The advanced platform presented here combines natural aspects of the microenvironment with tunable properties useful for bone tumor research. The role of bone marrow adipocytes in advanced prostate cancer is still poorly defined, due to a lack of relevant models. Therefore, in this study, bioengineered human bone tumor platforms are developed using GelMA hydrogels. Mineralized, adipose, and prostate cancer 3D microtissues are generated in vitro, before being implanted in vivo to create an advanced humanized fatty bone tumor microenvironment.