Bioprinted Cancer Model of Neuroblastoma in a Renal Microenvironment as an Efficiently Applicable Drug Testing Platform

Abstract

Development of new anticancer drugs with currently available animal models is hampered by the fact that human cancer cells are embedded in an animal-derived environment. Neuroblastoma is the most common extracranial solid malignancy of childhood. Major obstacles include managing chemotherapy-resistant relapses and resistance to induction therapy, leading to early death in very-high-risk patients. Here, we present a three-dimensional (3D) model for neuroblastoma composed of IMR-32 cells with amplified genes of the myelocytomatosis viral related oncogene MYCN and the anaplastic lymphoma kinase (ALK) in a renal environment of exclusively human origin, made of human embryonic kidney 293 cells and primary human kidney fibroblasts. The model was produced with two pneumatic extrusion printheads using a commercially available bioprinter. Two drugs were exemplarily tested in this model: While the histone deacetylase inhibitor panobinostat selectively killed the cancer cells by apoptosis induction but did not affect renal cells in the therapeutically effective concentration range, the peptidyl nucleoside antibiotic blasticidin induced cell death in both cell types. Importantly, differences in sensitivity between two-dimensional (2D) and 3D cultures were cell-type specific, making the therapeutic window broader in the bioprinted model and demonstrating the value of studying anticancer drugs in human 3D models. Altogether, this cancer model allows testing cytotoxicity and tumor selectivity of new anticancer drugs, and the open scaffold design enables the free exchange of tumor and microenvironment by any cell type.

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

“…Despite available new models and multidisciplinary approaches, appropriate comprehensive studies which compare different models (2D, 3D spheroid, 3D bioprinted and in vivo) from the same human cell lines are still missing [57].…”

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

“…(A) (B) Although 3D-bioprinting has been used in studies focusing on various forms of solid tumors, including neuroblastoma [66,67], melanoma [68,69], pancreatic cancer [55,70], non-small cell lung cancer [71], liver cancer [72], and osteosarcoma [73], the most prolific research has been conducted in breast cancer and glioma/glioblastoma models. The level of control over the spatial arrangement of cells, the possibility of multiple cell type use, and fine-tuning the biochemical and physical properties of biomaterials available through bioprinting allows generation of structures of a varied degree of complexity-from simple monocellular models to organoids and assembloids.…”

“…Although 3D-bioprinting has been used in studies focusing on various forms of solid tumors, including neuroblastoma [66,67], melanoma [68,69], pancreatic cancer [55,70], non-small cell lung cancer [71], liver cancer [72], and osteosarcoma [73], the most prolific research has been conducted in breast cancer and glioma/glioblastoma models.…”

The Evolution of Complex Muscle Cell In Vitro Models to Study Pathomechanisms and Drug Development of Neuromuscular Disease

“…Bioprinting provides the opportunity to build complex constructs through the precise positioning of different cell types, bioactive factors, and biomaterials of different architectural properties mimicking the structure of a specific tissue or organ [ 169 , 170 , 171 , 172 ]. For printing live cells, bioinks based on hydrogels have been employed as a carrier substance [ 173 ].…”