PharmD, PhD
PharmD, PhD
MD resident
PhD
Our research explores the genomic and molecular basis of pediatric liver tumors to advance knowledge and improve treatment.
In the Genomics of Pediatric Liver Tumors group, we study tumor evolution using data from patient clinical features, whole-genome and exome sequencing, bulk RNAseq, single-cell, and spatial transcriptomics. We focus primarily on hepatoblastoma (HB), the most common pediatric liver cancer, as well as pediatric hepatocellular carcinoma (HCC), fibrolamellar carcinoma (FLC), and hepatocellular adenoma (HCA).
We partner with clinicians across France to gather samples and address key research questions, and work with Japanese teams to validate findings. We develop computational tools to integrate multi-scale data, exploring tumor evolution and chemotherapy resistance (Figure 1).
Context:
Tumor cells carry molecular changes (mutations, chromosome alterations) that affect gene function. We use computational methods to find recurring altered genes driving cancer, which can be somatic (tumor-specific) or germline/mosaic (predisposing), especially in early childhood cancers.
Published results:
By analyzing 122 tumor samples from 84 patients using whole-genome or whole-exome sequencing, we pinpointed key driver alterations in pediatric liver cancers (Hirsch et al, Cancer Discov 2021) (Figure 2).
HB and HCC converge on pathways like Wnt/β-catenin and IGF2 but differ in alteration types: HB often have mutations (e.g., CTNNB1), while HCC show deletions (e.g., AXIN1). Some HB patients have germline APC mutations linked to familial adenomatous polyposis, and a somatic second hit (Morcrette et al, Oncoimmunology 2019). Rare driver alterations predict poor chemotherapy response and survival (Pire et al, Eur J Cancer 2024). Alterations at the 11p15.5 locus, causing IGF2 overexpression, are a major driver. We found mosaic 11p15.5 changes in ~20% of HB patients’ non-tumor liver, marking preneoplastic cells and affecting liver function (Pilet et al, Nat Commun 2023).
Ongoing projects:
We aim to identify new driver alterations of pediatric liver cancers by expanding our cohort analyzed by whole-genome sequencing and bulk RNAseq. We have specific projects to further explore mosaic alterations at the single-cell and spatial level.
Context:
Tumor evolution is a multi-step process driven by mutations under immune and treatment pressures, leading to diverse phenotypes. We study how clonal changes and phenotypes connect to tumor evolution and resistance.
Published results:
Using RNAseq on 100 HB samples, we defined three transcriptomic groups tied to differentiation, proliferation, and immune response (Hirsch et al, Cancer Discov 2021) (Figure 3a). Multiple samples from the same tumor showed varied phenotypes despite shared drivers, indicating plasticity. Chemotherapy boosts immune infiltration in ‘Hepatocytic’ tumors but not ‘Liver Progenitor’ ones. Single-cell analysis confirmed these groups, revealing a continuum of cell states and subclonal diversity (Roehrig et al, Nat Commun 2024) (Figure 3b).
Ongoing projects:
We currently explore the intra-tumor heterogeneity of hepatoblastoma at the spatially-resolved single-cell level, by combining high-plex immunofluorescence, single-nucleus RNAseq and spatial transcriptomics.
Context:
Hepatoblastoma is treated with cisplatin-based chemotherapy, but some cases resist treatment, with few therapeutic alternatives.
Published results:
Whole-genome sequencing revealed cisplatin’s SBS35 mutational signature (Figure 4a) in a subset of primary hepatoblastomas post-chemotherapy, associated with poor treatment response (Hirsch et al, Cancer Discov 2021 ; Pire et al, Eur J Cancer 2024). In primary tumors, SBS35 mutations were subclonal, meaning they appeared in only a fraction of tumor cells, specifically within ‘Liver Progenitor’ sectors, while ‘Hepatocytic’ and ‘Mesenchymal’ areas lacked them. In contrast, relapse samples showed thousands of clonal SBS35 mutations, present in all tumor cells, indicating relapses arise from a single resistant cell that accumulated cisplatin-induced mutations during treatment (Figure 4b). Overall, the longitudinal analysis of cisplatin-induced mutations, integrated with the transcriptomic classification, pinpoints the ‘Liver Progenitor’ cells as being chemoresistant and at the origin of relapses.
Targeting PLK1, a ‘Liver Progenitor’ marker, reduced tumor growth in proof-of-concept experiments developed with Sandra Rebouissou’s group (Hirsch et al, Cancer Discov 2021).
Ongoing projects:
We’re refining detection of cisplatin mutations with machine learning and, with Sandra Rebouissou’s group, seeking drugs to reverse chemoresistance.
PhD
MD
MD - PhD
Roehrig A, Hirsch TZ, Pire A, Morcrette G, Gupta B, Marcaillou C, Imbeaud S, Chardot C, Gonzales E, Jacquemin E, Sekiguchi M, Takita J, Nagae G, Hiyama E, Guérin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugières L, Fresneau B, Zucman-Rossi J, Letouzé E. Nat Commun. 2024 Apr 8;15(1):3031. doi: 10.1038/s41467-024-47280-x. PMID: 38589411
Pire A, Hirsch TZ, Morcrette G, Imbeaud S, Gupta B, Pilet J, Cornet M, Fabre M, Guettier C, Branchereau S, Brugières L, Guerin F, Laithier V, Coze C, Nagae G, Hiyama E, Laurent-Puig P, Rebouissou S, Sarnacki S, Chardot C, Capito C, Faure-Conter C, Aerts I, Taque S, Fresneau B, Zucman-Rossi J. Eur J Cancer. 2024 Mar;200:113583. doi: 10.1016/j.ejca.2024.113583. Epub 2024 Feb 1. PMID: 38330765
Pilet J, Hirsch TZ, Gupta B, Roehrig A, Morcrette G, Pire A, Letouzé E, Fresneau B, Taque S, Brugières L, Branchereau S, Chardot C, Aerts I, Sarnacki S, Fabre M, Guettier C, Rebouissou S, Zucman-Rossi J. Nat Commun. 2023 Nov 6;14(1):7122. doi: 10.1038/s41467-023-42418-9. PMID: 37932266
Hirsch TZ, Pilet J, Morcrette G, Roehrig A, Monteiro BJE, Molina L, Bayard Q, Trépo E, Meunier L, Caruso S, Renault V, Deleuze JF, Fresneau B, Chardot C, Gonzales E, Jacquemin E, Guerin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugières L, Rebouissou S, Letouzé E, Zucman-Rossi J. Cancer Discov. 2021 Oct;11(10):2524-2543. doi: 10.1158/2159-8290.CD-20-1809. Epub 2021 Apr 23. PMID: 33893148
Hirsch TZ, Negulescu A, Gupta B, Caruso S, Noblet B, Couchy G, Bayard Q, Meunier L, Morcrette G, Scoazec JY, Blanc JF, Amaddeo G, Nault JC, Bioulac-Sage P, Ziol M, Beaufrère A, Paradis V, Calderaro J, Imbeaud S, Zucman-Rossi J. J Hepatol. 2020 May;72(5):924-936. doi: 10.1016/j.jhep.2019.12.006. Epub 2019 Dec 18. PMID: 31862487
APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures.
Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019. PMID: 31069152
PhD
MD, PhD
“Therapeutic Targets in liver tumors”, led by Sandra Rebouissou Ph.D. & Jean-Charles NAULT M.D Ph.D., develops an integrated approach that extends from the study of the molecular basis of tumor initiation and progression to applications of targeted treatment and the identification of biomarkers predicting the therapeutic response. For this purpose, they develop two main research axes:
1) translational studies based on screening of anti-tumor molecules on large collections of adult and pediatric human liver cancer cell lines characterized extensively at the molecular level, combined with genomic analysis of tumor samples from patients included in clinical trials in order to link tumor molecular alterations and microenvironment to the clinical therapeutic response.
2) basic studies aimed at modeling in cellulo and in vivo the genetic alterations identified in human tumors in order to better identify the driver genes and their role in liver oncogenesis, and to understand the mechanisms of oncogenic cooperations.
MD, PhD
PhD
MD
MD
MD
PharmD
APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547.
Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response. Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001.
Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.
Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6.
Note of caution: Contaminations of hepatocellular cell lines. Rebouissou S, Zucman-Rossi J, Moreau R, Qiu Z, Hui L. J Hepatol. 2017 Nov;67(5):896-897. doi: 10.1016/j.jhep.2017.08.002. Epub 2017 Aug 12.
PhD
Pleural mesothelioma is a rare tumor mainly linked to asbestos exposure, characterized by a poor prognosis and an urgent need for precision medicine strategies. Therefore, predicting response to current treatments and developing new therapies that account for the molecular and cellular heterogeneity of pleural mesothelioma is crucial. To meet these challenges, we are focusing our research on 3 major axes:
(1) Deciphering intra-tumour heterogeneity: Single-cell omics and emerging spatial omics approaches will help define the tumour cell subpopulations present in a single biopsy. This will allow us to better understand their plasticity and phenotypic evolution, as well as to dissect the landscape of immune and stromal cells composing the tumour microenvironment.
(2) Developing therapeutic strategy: Functional screening using knockdown and knockout approaches, along with pharmacogenomics studies using our large patient-derived primary cell line biobank will lead to the identification of new therapeutic targets and new effective anti-tumour drugs that consider the phenotypic diversity of tumours.
(3) Identifying biomarkers of response to treatment: We will uncover signatures or biomarkers that predict response to treatment through multi-omics integrated analysis of tumor sample collection from patients enrolled in clinical trials or treated in real-life settings.
These projects are carried out in partnership with several clinical departments and associations. Close collaborations with other research laboratories allow us to explore areas such as the contribution of specific immune subpopulations to treatment resistance in preclinical models, and the identification of risk factors for pleural mesothelioma beyond asbestos exposure.
Our research works has contributed to a better understanding of the molecular alterations but more importantly of the molecular heterogeneity of pleural mesothelioma. We were the first to propose a molecular classification of pleural mesothelioma that goes beyond the histologic classification and identifies specific molecular subtypes linked to mutational status. We also proposed a novel way to describe mesothelioma heterogeneity as a continuum using histo-molecular gradients that consider the main histologic types (epithelioid/sarcomatoid). We highlighted that these histo-molecular gradients identify tumours classified epithelioid at the histologic level, which are engaged towards the sarcomatoid phenotype. They do have strong prognostic value and may guide therapeutic strategies. Recent works have contributed to a better description of pleural mesothelioma anatomic intra-tumour heterogeneity. Importantly, we revealed genetic heterogeneity involving the major tumour suppressor gene NF2, as well as“hot” and “cold” immune profile of the tumour microenvironment depending on tumour positions in the thoracic cavity. Our results support the need to analyse multiple samples from distinct anatomical sites in order to estimate the prognosis or implement precision medicine strategies.
de Reynies et al, Clinical Cancer Research, 2014; Tranchant et al, Clinical Cancer Research, 2017; Blum et al, Nat Commun, 2019 ; Meiller Genome Med. 2021.
PhD
MD, PhD
MD, PhD
PharmD, PhD
FunGeST “Functional genomics of solid tumors”, directed by Jessica Zucman-Rossi, was created in 2005, as Inserm U674, it was renewed in 2009, 2014 as UMR1162, ranked “incontournable” by Inserm as a mixed structure endorsed by four entities: Inserm, Universities Paris Diderot, Paris Descartes and Paris Nord. It is currently located at the University Hematology Institute site in a building managed by the CEPH (Centre d’Etude du Polymorphisme Humain, Foundation Jean Dausset). Since January 2019, the lab take part of Centre de Recherche des Cordeliers Research Center – Inserm UMR S1138, and as been recently renewed in January 2024.
Jessica Zucman-Rossi, is professor of Medicine in Oncology (PUPHex) at the University Paris Descartes and HEGP, dedicated full-time for research. She has directed the Inserm U674, U1162, and UMRS1138 FunGeST team since 2007, and served as chairman of the Inserm scientific committee devoted to Oncology, Genetics and Bioinformatics from 2012 to 2016. She is editor at the Journal of Hepatology (2023 IF=26.8), and the executive secretary of the International Liver Cancer Association (ILCA). She is internationally recognized in the field of genomics of human cancers, and particularly in liver tumors. Since January 2019, Pr. Zucman-Rossi has been the director of the Cordeliers Research Center, and was renewed for another 5-years in 2024.
Our mission is to develop basic genomic approaches based on human tumors analyses to identify new mechanisms of tumorigenesis and to transfer this knowledge into biomarkers and therapeutic targets that could be introduced in clinical care. In particular, we aim to identify new genomic alterations and mechanisms of carcinogenesis. We also aim to identify new risk factors and genetic predispositions promoting the development of tumors. Our major fields of research are related to liver tumors, mesothelioma and HPV-related cancers, mainly in adults but also in children for liver tumors.
Our team is multidisciplinary mixing basic researchers in genomics, genetics, cell biology, and bioinformatics with clinicians.
Our major topics are all centered on “bench to bedside” discoveries and vice versa:
Our strategies are based on large tumor collections with extensive clinical annotation (PRB Hôpitaux Universitaires Paris-Seine-Saint Denis, M Ziol, and other CRB at APHP hospitals and a national network), the development of innovative integrative genomic analyses, and the transfer into clinical care for the benefit of the patients. We are also actively developing productive scientific collaborations at CRC, regional, national, international, and industrial levels.
The team include a total of 45 peoples organized in 6 groups with their founded projects:
We aim to develop scientific projects with specific objectives to integrate innovative tumor genomic characterizations with metabolism and immune response to identify new biomarkers and therapeutic targets useful for the patients. To this aim, we focus on 3 major types of cancer: liver, mesothelioma and renal carcinoma, in close collaboration with clinicians and pathologists. Thanks to our future moving at the Centre de Recherche des Cordeliers our team will benefit from close collaborations with other teams involved in Onco-Immunology, Metabolism and developing innovative genomic approaches.
