Non-genetic heterogeneity and phenotypic plasticity in neuroblastoma, from cellular models to patients

Host

Adriana Sánchez-Danés, PhD, Cancer and Stem Cell Biology Lab

Venue

Seminar Room

Abstract

In my presentation, I will discuss nongenetic heterogeneity and cell state plasticity in neuroblastoma. Neuroblastoma tumor cells from several cellular models can adopt two distinct molecular identities, noradrenergic and mesenchymal, defined by specific transcriptomic and epigenetic programs. Noradrenergic cells are driven by a core regulatory circuitry including PHOX2B, HAND2, and GATA3, key transcription factors of sympathetic neuron development, whereas mesenchymal cells display a neural crest–like epigenetic landscape associated with increased invasiveness and drug resistance. Importantly, these identities are not fixed, as some tumor cells may undergo spontaneous and reversible transitions driven by epigenetic reprogramming and strongly influenced by the microenvironment. I will highlight recent work from our team showing that YAP/TAZdependent
transcriptional programs control the noradrenergictomesenchymal transition through epigenome rewiring. Finally, I will discuss intra-tumor heterogeneity of cell identity in neuroblastoma patients.

Bio

Isabelle JanoueixLerosey is a team leader at Institut Curie in Paris, where she heads the research group “Tumor Biology and Oncogenesis of Neuroblastoma.” She is an internationally recognized leader in the field of neuroblastoma, a highly heterogeneous pediatric cancer for which patients with highrisk disease still face a poor prognosis. Her research aims to decipher the biological mechanisms underlying neuroblastoma initiation, progression, and relapse, with the ultimate goal of developing more effective therapeutic strategies. Her work has made major contributions to the understanding of neuroblastoma biology, particularly through the identification of tumorspecific genetic and epigenetic alterations. She played a pivotal role in the discovery of activating mutations in the ALK gene, a landmark finding that transformed the field by enabling targeted therapeutic approaches and led to the international TITAN clinical trial, which incorporates the ALK inhibitor lorlatinib into frontline treatment. More recently, her team demonstrated that neuroblastoma cells can adopt two distinct cellular identities driven by epigenetic reprogramming, with profound consequences for chemoresistance, invasiveness, and tumor relapse.

Ongoing work explores the molecular mechanisms underlying this plasticity, including the role of YAP/TAZ signaling. In parallel, her team investigates the tumor ecosystem, with a strong focus on the immune microenvironment, to identify novel immunotherapeutic strategies and understand how tumor–immune interactions shape disease progression. A third research axis addresses the cell of origin of neuroblastoma and how developmental context influences tumor behavior. The team combines cellular and mouse models with analyses of fresh patient samples and has strong expertise in stateoftheart omics and bioinformatics approaches. Isabelle JanoueixLerosey serves on several national and international scientific committees and advisory boards. Her scientific excellence has been recognized by multiple awards, including distinctions from the French Academy of Sciences and the French National Academy of Medicine. She has been elected last year at the European ANRA (Advances in Neuroblastoma Research Association) Advisory Board.

Register here.

About CR Colloquia Series

Champalimaud Research (CR) Colloquia Series is a seminar programme organised by the Champalimaud Centre for the Unknown to promote the discussion about the most interesting and significant questions in neuroscience and physiology & cancer with appointed speakers by the CR Community.