Heterogeneity and excitability of BRAFV600E-induced tumors is determined by Akt/mTOR-signaling state and Trp53-loss.
Neuro Oncol
; 24(5): 741-754, 2022 05 04.
Article
in En
| MEDLINE
| ID: mdl-34865163
ABSTRACT
BACKGROUND:
Developmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function.METHODS:
Intraventricular in utero electroporation in combination with the piggyBac transposon system was utilized to generate developmental brain neoplasms, which were comprehensively analyzed with regard to growth using near-infrared in-vivo imaging, transcript signatures by RNA sequencing, and neuronal activity by multielectrode arrays.RESULTS:
BRAF V600E expression in murine neural progenitors elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG) only in concert with active Akt/mTOR-signaling. Purely glial tumors resembling aspects of polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to generate anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter.CONCLUSION:
mTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Ganglioglioma
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Neuro Oncol
Journal subject:
NEOPLASIAS
/
NEUROLOGIA
Year:
2022
Document type:
Article
Affiliation country:
Germany