Our Research Projects

Modeling glioblastoma using human pluripotent stem cells

Glioblastoma is a heterogeneous disease. Recent multidimensional analyses identified new subtypes of pediatric glioblastomas (Schwartzentruber et al, Nature 2012; Wu et al., Nature Gen. 2012; Sturm et al, Cell 2016). These subtypes are defined by specific gene mutation and expression profiles; however their pathogeneses are largely unknown. We hypothesized that each subtype originates from different cell type of origin by different molecular mechanism. To test this hypothesis, we utilized human pluripotent stem cells (ES cells and iPS cells), which can be differentiated to various neural progeny, and developed new glioma models. So far, we have successfully created models of H3.3K27M-mutant pontine glioma (a.k.a. DIPG) and H3.3G34R-mutant cortical glioblastoma, and have shown the cell-type and region-specific effects of the driver mutations (Funato et al, Science 2014; Funato et al, Cell Stem Cell 2021).

Developing tailor-made therapies for glioblastoma

Glioblastoma is one of the most lethal tumor types with a median survival of 14 months. Recent studies indicate the heterogeneity of glioblastoma; however most patients are treated with the same or similar regimen regardless of genetic and molecular characteristics of tumors. By interrogating the subtype-specific mechanisms of gliomagenesis, our lab seeks to identify vulnerabilities of each glioblastoma subtype and develop new therapies and diagnostic tools.

Dissecting the role of human specific genes in glioblastoma

Human-specific duplicate genes are groups of genes that emerged during human evolution by chromosomal duplication. Our recent study found that a human specific gene family NOTCH2NL is up-regulated in G34R-mutant pediatric glioblastoma (Funato et al, Cell Stem Cell 2021). Our data show that the upregulation of NOTCH2NL enhances the Notch signaling pathway and contributes to tumorigenicity. This finding indicates tumor cells co-opt evolutionary pathways that lead to the large brain size of modern humans.