Abstract 320: 3D-bioprinting of biomimetic multicellular glioblastoma tissues enable modeling of tumor-immune interactions
Authors: Tang Min , Xie Qi , Gimple Ryan C. , Prager Briana C. , Qiu Zhixin , Schimelman Jacob , Wang Pengrui , Lee Derrick , Yu Aaron , Miller Tyler E. , Kidwell Reilly L. , Wan Xueyi , Tang Jing , Tam Trevor , Tian Jing , Sun Bingjie , Chen Shaochen , Rich Jeremy 
Published: September 2020

The glioblastoma is a complex ecosystem with multiple cell types and an extracellular matrix (ECM) unique to the brain. Dynamic interactions between tumor cells and other non-neoplastic cell types drive the progression of cancer and continuously remodel the local microenvironment. Some major non-neoplastic players in the glioblastoma microenvironment include blood vessels that support tumor growth, several resident central nervous system (CNS) cells such as astrocytes, neurons, and microglia, as well as tumor-associated macrophages, the most substantial non-neoplastic component of glioblastoma. While animal models retain the genomic signature and transcriptome of the original patient tumor tissue, the use of immunocompromised animals inherently limits investigation of the role of immune components within the glioblastoma tissue. Here, we developed a rapid 3D-bioprinting method to construct a clinically relevant multicellular in vitro model to recapitulate the complexity of the glioblastoma microenvironment. The 3D models made of brain-specific materials were constructed with a central core of glioblastoma stem cells, with or without macrophages, surrounded by the resident CNS cells, which served to mimic the brain parenchyma surrounding the tumor tissue. Gene expression and transcriptome analysis demonstrated that both the glioblastoma stem cells and the macrophage precursors responded to the 3D-bioprinted glioblastoma microenvironment and better resembled their counterparts in patient tumor tissue compared to sphere or suspension culture. Furthermore, the four-cell model with macrophages closely resembled patient transcriptional profiles predictive of patient prognosis and drug sensitivity, and better recapitulated the glioblastoma invasiveness and stemness compared to three-cell models without macrophages or sphere cultures. Finally, the 3D-bioprinted models also enabled whole genome CRISPR screening to identify unique functional dependencies not identified in sphere culture controls. The 3D-bioprinting method is highly scalable and reproducible. The multicellular glioblastoma model combines fine spatial control of brain-specific materials and multiple cell types to create a sophisticated human species-matched model that contains both neoplastic and non-neoplastic regions.

Citation Format: Min Tang, Qi Xie, Ryan C. Gimple, Briana C. Prager, Zhixin Qiu, Jacob Schimelman, Pengrui Wang, Derrick Lee, Aaron Yu, Tyler E. Miller, Reilly L. Kidwell, Xueyi Wan, Jing Tang, Trevor Tam, Jing Tian, Bingjie Sun, Shaochen Chen, Jeremy Rich. 3D-bioprinting of biomimetic multicellular glioblastoma tissues enable modeling of tumor-immune interactions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 320.