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Published on: January 26, 2013
A human embryonic stem cell-based model reveals the cell of origin of FOXR2-activated CNS neuroblastoma
Hitomi N Royston1,2, Autumn B Hampton2, Dhruv Bhagat2
1Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
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.
Insights
Central nervous system neuroblastoma (CNS NB-FOXR2) originates from medial ganglionic eminence progenitors. FOXR2 drives tumor growth by activating the MEK/ERK pathway, offering a therapeutic target.
Area of Science:
- Neuro-oncology
- Developmental neurobiology
- Cancer genomics
Background:
- FOXR2-activated central nervous system (CNS) neuroblastoma (CNS NB-FOXR2) is a recently identified brain tumor subtype.
- Elevated FOXR2 expression, often due to genomic rearrangements, characterizes this tumor.
- The precise pathogenic mechanisms and cell of origin for CNS NB-FOXR2 remain unclear.
Purpose of the Study:
- To identify the cell type of origin for CNS NB-FOXR2.
- To develop a model to study the molecular and cellular mechanisms of CNS NB-FOXR2 formation.
- To investigate the role of FOXR2 in tumor development and identify potential therapeutic targets.
Main Methods:
- Gene expression analysis of patient tumors to predict cell of origin.
- Development of a human embryonic stem cell-based model.
- In vivo tumorigenicity assays and molecular pathway analysis.
Main Results:
- CNS NB-FOXR2 tumors express lineage markers of the medial ganglionic eminence (MGE).
- FOXR2 overexpression promotes proliferation and tumorigenicity in MGE progenitors.
- FOXR2 activates the MEK/ERK signaling pathway by suppressing DIRAS3, a RAS inhibitor.
Conclusions:
- Medial ganglionic eminence (MGE) progenitors are identified as the cell of origin for CNS NB-FOXR2.
- FOXR2 drives CNS NB-FOXR2 development through MEK/ERK pathway activation.
- Targeting the MEK/ERK pathway, for example with trametinib, shows potential for treating CNS NB-FOXR2.
