We study 3 types of solid tumors using genomic approaches to better understand their molecular and clinical heterogeneity and develop new diagnostic and prognostic markers. For this we use the last advanced technologies in molecular biology associated to our expertise in bioinformatic.
The various activities of our lab and its members
Revealing HPV Insight Using Capture HPV and ViroCapt2 Analysis Within Immuneboost-HPV Cohort (NCT03838263)
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.
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.
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.
This study is the first GWAS analysis that identified new genetic polymorphisms associated with the risk of hepatocellular carcinoma in European patients with high alcohol intake. It has enlightened the role of the WNT/ß-catenin in the early step of hepatocarcinogenesis. Clinical use to predict the risk of HCC in cirrhotic patients was validated by the team in 2023 (Nahon et al, JHEP, 2023, IF=30).
This is a seminal integrated genomic analysis of pediatric liver tumors that enabled to discover several alterations new cancer driver genes, frequent pre-neoplastic somatic mosaicism in young children with hepatoblastoma, new mechanisms of resistance to cisplatin with the involvement of cell plasticity. These results pave the field of transferring genomic data in clinical practice.
This study highlighted the intra-tumoral molecular heterogeneity at the anatomical level in mesothelioma that must be taken into account for the implementation of precision medicine. It supports the need to analyse multiple tumor samples at distinct anatomical sites in the pleural cavity to guide therapeutic choice.
This publication illustrates our contribution and our exceptional activity in research fields during COVID19 pandemic. Specifically, in this study, the sensitivity of the new SARS-CoV-2 variant Delta to antibody neutralisation was evaluated and proved to be reduced. This particular period has allowed us to establish very fruitful collaborations (Hadjadj J. et al., Science 2020; Planas D. et al, Nat Med 2021; Bruel T. et al.. Nature Med 2021; Planas D. et al. Nature 2022).<br />
This work has demonstrated the power of screening 31 anti-tumor drugs on a large panel of 34 cell lines established from liver cancer patients. Integration with genomic, proteomic and transcriptomic data allowed the identification of new therapeutic targets linked to specific oncogenic alterations. This is seminal work for developing genomics-based precision therapies currently underway by JC Nault in clinical practice.
This study defined histo-molecular gradients that take into account both intra- and inter-tumor heterogeneity and propose a new way of thinking about the pathology of mesothelioma and more generally of cancer. The gradients are strongly associated with prognosis and can guide therapeutic strategies for mesothelioma.
This study is an important improvement of the molecular classification of hepatocellular adenoma we established in 2006 with the discovery of new molecular subtypes and tumor driver genes closely correlated to the clinical features of the patients. Based on this classification JC Nault developed a clinical trial (PHRC funding), and defined the relations with the hormonal context of the patients to refine the prevention of relapses (Demory et al, Hepatology 2022) and with specific phenotypes (Calderaro et al, NEJM 2018).
