Biology subjects

Bouteille, L.

Publications and source records attributed to Bouteille, L..

4 recordsLinked to original sources

bioRxiv2026

MYCN-induced lineage infidelity initiates SHH medulloblastoma-like tumors outside the canonical lineage of origin

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.

cancer biology↗

bioRxiv2026

System-level regulation of hierarchical transitions in a tumour lineage

The fundamental principles defining how cell state transitions are regulated along a tumour lineage to determine its cellular composition remain unclear. Here, we investigate how such transitions are controlled in a reductionist hierarchical brain tumour model. Quantitative analysis of 3D transition maps revealed that the differentiation of cancer stem cells (CSCs) into transit amplifying progenitors (TAPs) depends on the identity of their immediate neighbours. This is embodied in a transition rule that quantitatively predicts the probability to differentiate as a function of the proportion of TAP neighbours. Integrated into 3D simulations of tumour growth, this rule spontaneously recapitulates spatial segregation of CSCs in clusters and their stable proportion. We further show in vivo that CSC clustering protects the CSC pool from depletion driven by TAPs. We identify an EGFR-mediated relay mechanism that propagates the CSC-to-TAP transition across CSC clusters. In CSCs, the LRIG1-like EGFR inhibitor Kekkon1 dampens this propagation, ensuring continuous replenishment of the CSC pool. Collectively, these findings show how local fate regulation drives emergent segregation which in turn constrains CSC differentiation dynamics. This provides a conceptual framework to understand and exploit the tumours intrinsic differentiation potential by manipulating the determinants of its system-level features.

cancer biology↗

bioRxiv2025

RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway

One-third of skin melanomas arise from melanocytic nevi, benign skin lesions composed of clustered melanocytes. Benign nevi are associated with overactivation of the mitogen-activated protein kinase RAS/ERK pathway, resulting from driver mutations, most commonly in the BRAF or NRAS gene. However, this overactivation in melanocytes is insufficient to induce melanoma formation, as only a minority of benign nevi give rise to melanoma. Overactivation of the RAS/ERK pathway promotes genetic and epigenetic alterations by inducing aneuploidy, but the processes by which nevi evolve into melanoma via RAS/ERK pathway-dependent aneuploidy are only partially understood. Using single-nucleus RNA sequencing after overactivation of the RAS/ERK pathway in the chicken embryo, we discovered that RIPOR2 is a positive transcriptional target of this pathway, including in melanocyte precursors. Similar transcriptional control of RIPOR2 by RAS/ERK is conserved in human melanoma cells. RIPOR2 emerged as an attractive target because it encodes an atypical RHOA inhibitory protein involved in the development of physiologically multinucleated cell types. Multinucleation in cancer has been shown to promote aneuploidy, which correlates with tumor aggressiveness. We found that RIPOR2 is ectopically expressed in human nevi and skin melanomas and functionally promotes multinucleation in both an animal model and human tumor-derived cells, including melanoma cell lines. Our results suggest that RIPOR2 expression, downstream of RAS/ERK overactivation in skin melanocytes, promotes the emergence of multinucleated cells, a previously overlooked step in melanoma formation.

cancer biology↗

bioRxiv2021

Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis

Most human cancers demonstrate activated MAPK/ERK pathway signaling as a key tumor initiation step, but the immediate steps of further oncogenic progression are poorly understood due to a lack of appropriate models. Spinal cord differentiation follows caudal elongation in vertebrate embryos; both processes are regulated by a FGF8 gradient highest in neuromesodermal progenitors (NMP), where kinase effectors ERK1/2 maintain an undifferentiated state. FGF8/ERK signal attenuation is necessary for NMPs to progress to differentiation. We show that sustained ERK1/2 activity, using a constitutively active form of the kinase MEK1 (MEK1ca) in the chicken embryo, reproducibly provokes neopasia in the developing spinal cord. Transcriptomic data show that neoplasia not only relies on the maintenance of NMP gene expression, and the inhibition of genes expressed in the differentiating spinal cord, but also on a profound change in the transcriptional signature of the spinal cord cells leading to a complete loss of cell-type identity. MEK1ca expression in the developing spinal cord of the chicken embryo is therefore a tractable in vivo model to identify the critical factors fostering malignancy in ERK-induced tumorigenesis.

developmental biology↗