MYCN-induced lineage infidelity initiates SHH medulloblastoma-like tumors outside the canonical lineage of origin
Abstract
Amplification and high expression of MYCN and MYC are recurrent features of medulloblastoma and other pediatric cancers, yet how these proto-oncogenes interact with developmental programs to initiate tumorigenesis remains unclear. Here, we combine the experimental accessibility of the avian embryo with single-cell transcriptomics to investigate how MYCN overexpression reshapes cerebellar lineage trajectories. While MYCN broadly promotes transient overproliferation, enhanced biosynthesis and delayed neural maturation, we find that these effects are insufficient to drive tumorigenesis. Instead, tumorigenic competence is restricted to a discrete population of ATOH1 + isthmic progenitors, which reproducibly expands into extracerebellar tumors that transcriptionally resemble SHH medulloblastoma, partially recapitulating the granule cell lineage hierarchy. By reconstructing the earliest stages of tumor initiation, we show that MYCN first expands these progenitors and then redirects them toward a hybrid PAX6⁺ granule cell progenitor-like state. Blocking PAX6 transcriptional activity abolishes tumorigenesis of the reprogrammed population, demonstrating that cooption of this lineage program is functionally required for tumor growth. Our findings reveal that MYCN-induced oncogenicity in the cerebellum proceeds through a three-step temporal sequence driven by the erosion of lineage restrictions.
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BibTeX
@misc{bouteille2026mycninduced,
title = {{MYCN-induced lineage infidelity initiates SHH medulloblastoma-like tumors outside the canonical lineage of origin}},
author = {Lauranne Bouteille and William Fargues and Paul de Boissier and Guillaume Girard and Mehdi Saadaoui and Cédric Maurange},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.07.743303},
url = {https://hal.science/hal-05783810v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - MYCN-induced lineage infidelity initiates SHH medulloblastoma-like tumors outside the canonical lineage of origin
AU - Lauranne Bouteille
AU - William Fargues
AU - Paul de Boissier
AU - Guillaume Girard
AU - Mehdi Saadaoui
AU - Cédric Maurange
PY - 2026
DA - 2026/08/10
PB - HAL
DO - 10.64898/2026.08.07.743303
UR - https://hal.science/hal-05783810v1
AB - Amplification and high expression of MYCN and MYC are recurrent features of medulloblastoma and other pediatric cancers, yet how these proto-oncogenes interact with developmental programs to initiate tumorigenesis remains unclear. Here, we combine the experimental accessibility of the avian embryo with single-cell transcriptomics to investigate how MYCN overexpression reshapes cerebellar lineage trajectories. While MYCN broadly promotes transient overproliferation, enhanced biosynthesis and delayed neural maturation, we find that these effects are insufficient to drive tumorigenesis. Instead, tumorigenic competence is restricted to a discrete population of ATOH1 + isthmic progenitors, which reproducibly expands into extracerebellar tumors that transcriptionally resemble SHH medulloblastoma, partially recapitulating the granule cell lineage hierarchy. By reconstructing the earliest stages of tumor initiation, we show that MYCN first expands these progenitors and then redirects them toward a hybrid PAX6⁺ granule cell progenitor-like state. Blocking PAX6 transcriptional activity abolishes tumorigenesis of the reprogrammed population, demonstrating that cooption of this lineage program is functionally required for tumor growth. Our findings reveal that MYCN-induced oncogenicity in the cerebellum proceeds through a three-step temporal sequence driven by the erosion of lineage restrictions.
ER -