Central nervous system tumors and three-dimensional cell biology: Current and future perspectives in modeling

Table 4 Organoid and organoid-on-a-chip models

Ref.	Model system	System cell origin	Tumor type	Relevant genes	Results summary
Bian et al[38], 2018	neoCOR	hESCs	CNS-PNET; GBM	Amplified expression of MYC; Differential expression of GBM associated gene aberrations (GBM-1, GBM-2, and GBM-3)	neoCOR used to test gain- and loss of-function mutations, singly or in combination; generation of CNS-PNET or GBM xeno-transplantable tumors
Ogawa et al[58], 2018	Human cerebral organoids	hESC	GBM	RAS activation and TP53 deletion	Generation of tumors in cerebral organoids using CRISPR/Cas9 technology; tumors exhibited invasive phenotype and replicated the hallmarks of tumorigenesis in vivo
Ballabio et al[59], 2020	Human cerebellar organoids	Human induced pluripotent stem cell (iPSC)	Medulloblastoma (MB) subgroup 3	Overexpression of GFI1/c-MYC (GM) and OTX2/c-MYC (OM) gene combinations	OM as a novel driver gene combination required for Group 3 MB tumorigenesis; GM and OM overexpression induces tumor formation in mouse cerebellum; SMARCA4 and Tazemetostat reduces OM tumorigenesis
Linkous et al[60], 2019	GLICO	hESCs; iPSCs	GBM	-	GLICO recapitulate primary human GBM with in a primitive brain microenvironment; GSCs exhibit high resistance to drug and radiation-inducedgenotoxic stress; GSCs form tumor by relocating to the human cerebral organoid, invasion and proliferation within themicroenvironment of the GLICO
Akay et al[61], 2018	Microfluidic chip	Patient primary human GBM multiforme specimens	GBM	-	Generation of brain cancer chip that exhibit diffusion prevention mechanism to culture GBM-patient derived 3D spheroids; treatment with TMZ and bevacizumab (Avastin, BEV) in combination enhanced GBM cell death compared to TMZ alone
Ayuso et al[62], 2017	Microfluidic chip	U-251 MG human GBM cell line	GBM	-	Generation of microfluidic device to behavior models that simulate blood flow through the tumor; deprivation of nutrients and oxygen induces pseudopalisade formation; pseudopalisading process renders GBM cells to become of more aggressive behavior
Cui et al[63], 2018	Microfluidic chip	GL261 and CT-2A mouse glioma cell lines	GBM	-	Generation of microfluidic angiogenesis model that simulate GBM tumor angiogenesis and macrophage-associated immunosuppression within GBM tumor microenvironment; GL261 and CT-2A GBM-like tumors promote angiogenesis through driving M2-like macrophage polarization; TGF-b1, and surface integrin (avb3) endothelial-macrophage interactions regulates inflammation-mediated angiogenesis through Src-PI3K-YAP signaling; inhibition of integrin (avb3) and cytokine receptor (TGFb-R1) repress GBM tumor neovascularization
Lin et al[64], 2018	Microfluidic chip	Patient derived GSCs	GBM	-	Generation of glioma perivascular niches on a chip; Perivascular niches maintain the pluripotent state of GSCs; Stronger chemoresistance of GSCs against TMZ associates with endothelial cell co-culturing, GSCs neurosphere formation and the expression of 6-O-methylguanine and Bmi-1 gene
Yi et al[65], 2019	Bio-printed chip	Patient primary human GBM specimens	GBM	-	Generation of complex cancerous-tissue constructs constituting brain ECM composition, oxygen gradient-generating system, cancer-stroma structure; exhibited patient-specific response upon the treatment with drug combinations, chemoradiation and TMZ

2-D: Two dimensional; 3-D: Three dimensional; CNS-PNET: Central nervous system primitive neuroectodermal; CSC: Cancer stem cell; GBM: Glioblastoma; GLICO: Cerebral organoid glioma; GSCs: Glioma stem cells; hESC: Human embryonic stem cells; NeoCOR: Neoplastic cerebral organoid; PI3K: Phosphatidylinositol 3 kinase; PNET: Primary neuroectodermal tumor; TGF: Transforming growth factor; TMZ: Temozolomide.