A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors

Abstract

Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs.

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

“…Consistent with our previous study that linked C19MC expression with Sonic hedgehog (SHH) and WNT developmental signaling in ETMRs (Li et al, 2009;Picard et al, 2012), we observed enrichment of multiple SHH and WNT pathway components, including GLI2 and AXIN2, in RIP studies indicating that C19MC may act via LIN28A to modulate these lineage-determining pathways. Interestingly embryonal tumors with histological and transcriptional features resembling human ETMRs have been reported by concurrent activation of SHH and WNT signaling in murine neural precursors (Neumann et al, 2017). However, these murine tumors lacked characteristic LIN28A expression patterns seen in human tumors, indicating that alternative strategies may be needed to model ETMRs.…”

Stalled developmental programs at the root of pediatric brain tumors

“…High LIN28A and low OLIG2 levels, gain of chromosome 2 42 , and a very distinctive DNA methylation profile are hallmarks of ETMRs 8,9 . The cell of origin is unknown, although a Sox2+/Pax6+ apical radial glia of the cortical ventricular zone has been postulated as a potential source of ETMRs 43 .…”

ETMR: a tumor entity in its infancy

“…Possibly TTYH1 plays a role in the differentiation of neural stem cells during brain development [70,143], where TTYH1 is mainly expressed in neural stem cells, neurons and astrocytes [141]. The cell of origin of ETMRs is currently not known, but there are indications that ETMRs resemble a broad spectrum of developmental stages ranging from neural stem cells and early radial glia to a more differentiated lineage such as astrocytes and neurons based on histology [32,43,77], expressed markers [76,98,124], and single cell RNA sequencing [64]. It was proposed that loss of TTYH1 expression during development can lead to loss of C19MC expression [64]; however, it remains to be elucidated how this loss in expression can occur.…”