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

Abstract

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.

Defining the challenges and opportunities for using patient‐derived models in prostate cancer research

“…68 Methacrylated gelatin (GelMA) has been successfully used for co-cultures of prostate cancer cells lines with cells from the TME, and for automated protocols with bioprinting. [69][70][71] Therefore, this approach holds great potential for tackling the next step of introducing patient-derived cells.…”

“…Semi‐synthetic hydrogels, like methacrylated or thiolated gelatin, combine the advantages of natural matrices—such as low immunogenicity and integrin‐binding motifs—with the tailored characteristics of synthetic hydrogels, including their customizable chemical and physical properties 68 . Methacrylated gelatin (GelMA) has been successfully used for co‐cultures of prostate cancer cells lines with cells from the TME, and for automated protocols with bioprinting 69–71 . Therefore, this approach holds great potential for tackling the next step of introducing patient‐derived cells.…”

Biomimetic Microenvironmental Stiffness Boosts Stemness of Pancreatic Ductal Adenocarcinoma via Augmented Autophagy

“…Hydrogels with Different Stiffness. GelMA, as an acrylamide-modified gelatin (local hydrolysate of collagen) with excellent biological characteristics, has been widely used to resemble the microenvironment of multiple solid tumors, 32,34,35 and also acts as a mechanical interaction mimic platform as reported 36 although it may not be sufficient to accurately describe collagen biochemistry. From a processing perspective, GelMA hydrogels with tunable mechanical properties can be easily constructed by adjusting the UV exposure time and concentrations.…”

“…GelMA hydrogels are easily formed primarily via covalent bonds under UV/vis light photopolymerization. Recently, in the research of malignant tumors, such as colorectal cancer, 30 ovarian cancer, 31 and prostate cancer, 32 GelMA was widely utilized to simulate the matrix stiffness of healthy and pathological conditions. Biomimetic matrix stiffness based on the GelMA hydrogel played an essential role in the behavior and phenotype of tumor cells, such as proliferation, invasiveness, chemoresistance as well as stemness.…”

Interpenetrating network hydrogels for studying the role of matrix viscoelasticity in 3D osteocyte morphogenesis

“…Lower stiffnesses promoted osteogenic differentiation of MC3T3 cells in 3D gelatin hydrogels (0.58 vs. 1.47 kPa) and increased mineral deposition for primary osteoprogenitor cells in gelatin methacryloyl (GelMA) gels (6.3 vs. 16.3 and 40.2 kPa). 11,12 However, the viscoelastic nature of native osteoid tissue 13 is often overlooked and thus, the effect of varying matrix stress relaxation on osteocyte differentiation has not been investigated to date.…”