A human embryonic stem cell-based model reveals the cell of origin of FOXR2-activated CNS neuroblastoma.

Background: FOXR2-activated central nervous system (CNS) neuroblastoma (CNS NB-FOXR2) is a recently identified subtype of brain tumor characterized by the elevated expression of the transcription factor FOXR2 mainly due to genomic rearrangements. However, the precise pathogenic mechanisms, including the cell type of origin, remain elusive.

Methods: A gene expression analysis of patient tumors was performed to identify putative cell types of origin. Based on this prediction, a new human embryonic stem cell-based model was developed to validate the origin and to examine the molecular and cellular mechanisms underlying the formation of CNS NB-FOXR2.

Results: Our data showed that CNS NB-FOXR2 tumors express a high level of lineage marker genes associated with the medial ganglionic eminence (MGE), a transient structure located in the developing ventral forebrain. Our model confirmed the cell-type-specific effect of FOXR2 on the proliferation and in vivo tumorigenicity. Additionally, we found that FOXR2 overexpression activated the MEK/ERK signaling pathway through a suppression of the endogenous RAS inhibitor DIRAS3. The MEK inhibitor trametinib suppressed the proliferation of FOXR2-expressing MGE progenitors more than nonexpressing cells.

Conclusions: Our study collectively demonstrates that MGE progenitors are the cell of origin of CNS NB-FOXR2 and that FOXR2 activates the MEK/ERK signaling pathway, providing a potential therapeutic target.