Biology subjects

Janoueix-Lerosey, I.

Publications and source records attributed to Janoueix-Lerosey, I..

3 recordsLinked to original sources

bioRxiv2026

ALK variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner

High-risk neuroblastoma remains a major clinical challenge despite intensive multimodal treatment. Alterations in the anaplastic lymphoma kinase (ALK) gene are frequent in NB and correlate with poor outcome. ALK-F1174L and ALK-R1275Q are the most prevalent activating mutations, but their specific effects on tumor behavior remain unclear. Here, we compared the impacts of ALK-wild-type (wt), ALK-F1174L and ALK-R1275Q in several NB xenograft models. In the SK-N-Be2c model, ALK-F1174L mediated numerous transcriptomic alterations without affecting tumor behavior. In GIMEN cells, only ALK-F1174L and ALK-R1275Q conferred tumorigenicity with distinct growth kinetics and transcriptional programs. In the mesenchymal SH-EP model, ALK variants induced distinct phenotypes, with ALK-wt and ALK-F1174L promoting partial transition toward neuroblastic identity. All ALK variants induced lung metastases, but with allele-specific dissemination patterns. Transcriptomic profiling of SH-EP tumors and corresponding metastases revealed partly opposing pathway regulation between ALK-F1174L and ALK-R1275Q. Overall, ALK variants differentially modulate NB behavior in a context-dependent manner.

cancer biology↗

bioRxiv2021

Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces a mesenchymal phenotype. Our results document spontaneous plasticity in several models between both identities and show that plasticity relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Consistently, tumor cells with a mesenchymal identity are not detected in a series of PDX models. Further study of the intra-tumor noradrenergic heterogeneity reveals two distinct cell populations exhibiting features of chromaffin-like or sympathoblast-like cells. This work emphasizes that both external cues of the environment and intrinsic factors control plasticity and cell identity in neuroblastoma.

cancer biology↗

bioRxiv2019

Transcriptional programs define intratumoral heterogeneity of Ewing sarcoma at single cell resolution

EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive heterogeneity of transcriptional programs. Here, we combined independent component analysis of single cell RNA-sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus defined an exquisitely specific and direct, super-enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation was associated with a well-defined range of EWSR1-FLI1 activity; moreover, cells with a high EWSR1-FLI1 activity presented a strong oxidative phosphorylation metabolism. In contrast, a subpopulation of cells from below and above optimal EWSR1-FLI1 activity was characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within Ewing tumors.

cancer biology↗