The FunGeST team at the Cordeliers Research Centre is proud to share that our group leader, Professor Jessica Zucman-Rossi, has been honoured with the 2025 EASL Recognition Award at the annual congress of the European Association for the Study of the Liver (EASL), a leading international event in hepatology.

This prestigious award recognises both the excellence of her scientific contributions and her strong commitment to collaborative, inclusive, and open research.

What I love most in research is the joy of collective discovery. Sometimes, something clicks, and this is a piece of the puzzle that falls into place that makes our understanding grow. When you begin to experience this, you are completely addicted to research. This type of discovery would not be possible without my team.

Warm congratulations to Professor Jessica Zucman-Rossi on this inspiring recognition, which resonates deeply with the entire Cordeliers Research Centre community!

Revealing HPV Insight Using Capture HPV and ViroCapt2 Analysis Within Immuneboost-HPV Cohort (NCT03838263)

ABSTRACT

Background. Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease.
Methods. All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated.
Results. High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0–208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with ‘Liver Progenitor’ (p = 0.00049, p < 0.0001) and ‘Immune Cold’ (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic ‘Immune Cold’ and Liver Progenitor’ as a predictor of survival independent of the clinical features.
Conclusions. Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features.

Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

ABSTRACT

Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display IGF2 overexpression and H19 downregulation together with an alteration of the liver zonation. Moreover, mosaic livers’ microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.

ABSTRACT

Background. Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma.
Methods. We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10⁻⁶) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts.
Findings. The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10⁻⁸) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10⁻¹⁰), PNPLA3 (rs738409; p=9·29 × 10⁻⁷), and HSD17B13 (rs72613567; p=2·49 × 10⁻⁴). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10⁻³), TM6SF2 (rs58542926; p=4·06 × 10⁻⁵), and PNPLA3 (rs738409; p=1·17 × 10⁻⁴). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10⁻¹⁰), TM6SF2 (1·77, 1·52–2·07; p=3·84×10⁻¹³), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10⁻¹⁰). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis.
Interpretation. WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.