| dc.description.abstract |
<p>Brain tumors are an incredibly diverse group of neoplasms, as evidenced by their
varied locations in the brain, histological characteristics, and genetic alterations.
Brain tumor heterogeneity can be potentially explained by distinct oncogenic events
or cells-of-origin, or by region-specific intrinsic or extrinsic factors. Brainstem
Glioma (BSG) is a particularly deadly brain tumor, afflicting 200-300 children in
the United States each year. High-grade BSG (also known as Diffuse Intrinsic Pontine
Glioma, DIPG) cannot be surgically removed, and the standard treatment of radiation
therapy provides only temporary relief from symptoms. The past 5 years has witnessed
a dramatic increase in knowledge regarding the biological basis of this disease along
with the realization that BSG is distinct from other more common types of glioma,
such as cerebral cortex glioma (CG). It was the goal of this study to investigate
the regional differences in gliomas arising in the brainstem versus the cerebral cortex,
using mice as a model system, and to begin to understand the contributions of the
various possible sources of heterogeneity.</p><p> </p><p>In doing so, we have uncovered
region-specific gene expression patterns in these two types of pediatric gliomas that
are apparent even when the initiating genetic alterations and cell-of-origin are kept
constant. Focusing on the <italic>paired box 3</italic> (Pax3) gene, which is expressed
at higher levels in BSG than CG, we have found that Pax3 expression not only characterizes
mouse BSGs driven by PDGF signaling, Ink4aARF-loss, p53-loss, and H3.3-K27M expression,
but also identifies a novel subset of human BSGs that are associated with <italic>PDGFRA</italic>
alterations and wild type <italic>ACVR1</italic> and that commonly harbor <italic>TP53</italic>
alterations and the H3.3-K27M mutation. </p><p>As Pax3 plays a pro-tumorigenic role
in other types of cancer, we hypothesized that Pax3 expression contributes to the
brainstem gliomagenesis process as well. By utilizing mouse models, we found that
Pax3 inhibits apoptosis and promotes proliferation of Nestin-expressing brainstem
progenitor cells <italic>in vitro</italic> and enhances PDGF-B-driven BSG <italic>in
vivo</italic>. Furthermore, we speculate that Pax3 expression may be a marker for
Wnt pathway activation in BSG, which is targetable via pharmacologic agents. Indeed,
a subset of Wnt inhibitors tested effectively slowed the growth of BSG cells <italic>in
vitro</italic>, however cross talk with the Shh pathway might indicate that dual Wnt
and Shh inhibition is necessary.</p><p>In addition, the regional expression pattern
of Pax3 in gliomas correlates with its expression in normal murine brain development,
leading us to hypothesize that Pax3 progenitor cells in the neonatal brainstem can
serve as a cell-of-origin for BSG. We discovered that targeting Pax3 progenitors
with PDGF-B overexpression and Ink4aARF- or p53-loss induces high-grade BSG that physiologically
resemble the human disease. This novel and distinct model of BSG may be utilized in
the future for preclinical studies.</p><p>The identification of Pax3 as a regional
marker of mouse and human BSG has led to the discovery of a novel subset of the human
disease, the identification of a novel oncogene contributing to pathogenesis, and
the characterization of a novel cell-of-origin with the potential to give rise to
the disease. This information contributes significantly to the current understanding
of the mechanisms and cellular origins of BSG, and will hopefully instruct future
investigations into how to better treat this disease.</p>
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