[R03] A NOVEL GEMM TO ELUCIDATE THE ROLE OF CHAF1A IN NEUROBLASTOMA DEVELOPMENT
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2028-05-31
Importo max: 160.500 EUR
Paese: US
Descrizione
PROJECT SUMMARY:
This proposal focuses on the fundamental understanding on how the CHAF1A oncogene drives molecular
mechanisms, cellular signaling, and metabolic processes in the oncogenesis of neuroblastoma (NB). NB is an
aggressive pediatric cancer, which accounts for 15% of pediatric cancer mortalities. High-risk NB is thought to
arise from a small number of recurrent genetic alterations that block the ability of neural crest cells (NCCs) to
differentiate. To assess the molecular mechanisms governing NC differentiation, our laboratory has established
a definitive role of the epigenetic regulator CHAF1A in blocking NC differentiation and driving NB oncogenesis.
In this proposal, we will determine the impact of CHAF1A on NB initiation and progression. To accomplish this
goal, we propose to develop a novel CHAF1A-driven genetically-engineered mouse model (GEMM) of NB and
test the impact of CHAF1A on NB incidence, histology and metastasis, and the tumor immune microenvironment
(TIME). We hypothesize that CHAF1A will increase de novo incidence of NB, reduce mouse survival, and
promote a suppressive TIME. By developing a novel GEMM of NB and employing innovative technology
(including ATAC-seq, lipidomics, and scRNA-seq), we will: 1- elucidate the role of CHAF1A in NB tumor initiation
and progression; and 2- determine the impact of CHAF1A on MYCN-induced oncogenesis. These findings will
provide a novel view on the molecular mechanisms driving NB initiation, and will have high clinical implications,
informing future differentiation-based interventions for high-risk NBs.
Istituzione: BAYLOR COLLEGE OF MEDICINE
PI: Eveline Barbieri
Progetto: 1R03NS140939-01A1
Settori: National Institute of Neurological Disorders and Stroke
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