Team 06 - MIRCADE, Methods and Innovations for the Research in Pediatric Cancers.

Équipe 06 – MIRCADE (Méthodes et Innovations pour la Recherche sur les Cancers de l’Enfant).

The MIRCADE team studies the biology of several solid tumors in children, including hepatoblastoma, H3K27M mutated diffuse midline glioma (or DIPG) and Wilms’ tumor (or nephroblastoma). We are interested in the role played by certain signaling pathways (e.g. Wnt/beta-catenin, MAPK, ERK…), microRNAs and genes, especially those involved in lipid and energetic metabolism, beta-catenin stability and gene transcription. We are also working on drug repositioning and the development of new therapeutic approaches. We use many cell (cell culture in 2D or as spheroid) and animal models, including mouse, chicken embryo, Xenopus embryo and Zebrafish. We are also developing projects on a new discipline that we have called “Onconanotomy” which aims at studying the 3D architecture of tumor tissues.  

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Keywords

cell biology, cancer, pediatrics, child, hepatoblastoma, brainstem tumor, Wilms tumor, drug repositioning, molecular signaling, metabolism, lipids

News


Projects

1- Role of the DDR1 collagen receptor in the development of renal tumors

Wilms tumor develops from renal embryonic cells which will form pre-cancerous lesions, called quiescent and then hyperplastic nephrogenic rests, which will transform into tumors composed of 3 cellular contingents, epithelial, stromal and blastematous. A proteomics study showed that different collagens and/or their signaling pathways were decreased in tumors compared to quiescent nephrogenic rests. The restoration of signaling pathways induced by DDR1 after binding of fibrillar collagens showed a strong decrease in cell proliferation and migration, 2 very important steps for tumor development. Similar results were also obtained for adult renal carcinomas.
In perspective, we will focus on the roles of DDR1 in the recruitment and activation of immune cells within kidney tumors. At the same time, we will study the impact of the extracellular matrix in the resistance to treatment of renal cancers in children and adults.


Project members

Noteworthy publications
The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development.
Majo S, Auguste P
Cancers ; 2021 Apr 06

2- Deciphering the 3D organization of tumor tissues

The biological components of tumor tissue are now relatively well known. They include for instance tumor cells, immune cells and blood capillaries. However, the 3D organization of these tissues is poorly known and the bio-architectural parameters defining the internal structure of a tumor remains unknown. In a paper published in Communications Biology, our team dissected the organization of a hepatoblastoma tumor using “Serial Block face-scanning electron microscopy” volumetric imaging technology, deep/machine learning, applied mathematics and infographics. This pilot study shows for the first time that blood capillaries and bile canaliculus-like structures influence the size, planar alignment and orientation of tumor cells within the tissue. This work paves the way for a whole new field of research called Onconanotomy.

 

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Project members

Noteworthy publications
Deciphering tumour tissue organization by 3D electron microscopy and machine learning.
de Senneville BD, Khoubai FZ, Bevilacqua M, Labedade A, Flosseau K, Chardot C, Branchereau S, Ripoche J, Cairo S, Gontier E, Grosset CF
Communications biology ; 2021 Dec 13

3- Crosstalk between energy and lipid metabolisms and immuno-oncology of liver cancer

The aim of this axis of research is to understand energy and lipid metabolic adaptation of liver cancer cells and the crosstalk with innate immunity in the tumoral microenvironment. We have particular interest of assessing the benefit of available hypolipidemic drugs (statins and ati-PCSK9) to remodel lipid metabolism as a potential approach to treat liver cancers. Our ongoing results show profound anti-tumoral effects of these drugs in cell models as well as in in vivo models.
We also study the metabolic pathway of tryptophan/kynurenin/NAD and its impact in modulating immunosuppression of macrophages.

Figure: Crosstalk between metabolism and innate immunity within the classically activated M1 (antitumor-like macrophages) and the alternately activated M2 (protumor-like macrophages) (left) and overview of lipid metabolism in the liver (right).

 

          

 


Project members

Noteworthy publications
Targeting Lipid Metabolism in Liver Cancer.
Alannan M, Fayyad-Kazan H, Trézéguet V, Merched A
Biochemistry ; 2020 Oct 20

4- Anticancer drug repositioning in the treatment of childhood H3K27-altered diffuse midline glioma

Several of our projects aim at testing and validating the efficacy of anticancer agents, alone or in combination, in the treatment of childhood cancers. To validate the efficacy of these compounds, we use several animal models including the mouse, the chicken embryo, the Xenopus embryon and the Zebra fish. A first patent was filed in September 2021 following the discovery of the efficacy of the GSK126 + Statin combination in the treatment of infiltrating brainstem glioma (DIPG or also known as K3K27-altered Diffuse Midline glioma).

Figure: Synergistic effect GSK126 and inhibitors of cholesterol biosynthesis pathway enzymes on DMG tumor development in mice.

https://academic.oup.com/view-large/figure/340497140/vdac018f0006.jpg

  


Project members

Noteworthy publications
An EZH2 blocker sensitizes histone mutated diffuse midline glioma to cholesterol metabolism inhibitors through an off-target effect.
Rahal F, Capdevielle C, Rousseau B, Izotte J, Dupuy JW, Cappellen D, Chotard G, Ménard M, Charpentier J, Jecko V, Caumont C, Gimbert E, Grosset CF, Hagedorn M
Neuro-oncology advances ; 2022 Mar 01

5-LIM homeobox-2 suppresses hallmarks of adult and pediatric liver cancers

Hepatocellular carcinoma and hepatoblastoma are two liver cancers characterized by gene deregulations, chromosomal rearrangements, and mutations in Wnt/beta-catenin (Wnt) pathway-related genes. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis and liver development. LHX2 is oncogenic in many solid tumors and leukemia but its role in liver cancer is unknown. We analyzed the expression of LHX2 in hepatocellular carcinoma and hepatoblastoma samples using various transcriptomic datasets and biological samples. The role of LHX2 was studied using lentiviral transduction, in vitro cell-based assays (growth, migration, senescence, apoptosis), molecular approaches (phospho-kinase arrays, RNA-seq), bioinformatics and two in vivo models in chicken and Xenopus embryos. We found a strong connection between LHX2 down-regulation and Wnt activation in these two liver cancers. In hepatoblastoma, LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors and low patients’ survival. Forced expression of LHX2 reduced the proliferation, migration and survival of liver cancer cells in vitro through the inactivation of MAPK/ERK and Wnt signals. In vivo, LHX2 impeded the development of tumors in chick embryos and repressed the Wnt pathway in Xenopus embryos. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 mediated the disassembling of beta-catenin/T-cell factor 4 complex and induced expression of multiple inhibitors of Wnt (e.g. TLE/Groucho) and MAPK/ERK (e.g. DUSPs) pathways. Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.

Figure: Regulation of MAPK/ERK and Wnt signals by LHX2 in hepatoma cells.

https://www.karger.com/Journal/Issue/281478

 

    


Project members

Jobs offers


Team’s noteworthy publications

An EZH2 blocker sensitizes histone mutated diffuse midline glioma to cholesterol metabolism inhibitors through an off-target effect.
Rahal F, Capdevielle C, Rousseau B, Izotte J, Dupuy JW, Cappellen D, Chotard G, Ménard M, Charpentier J, Jecko V, Caumont C, Gimbert E, Grosset CF, Hagedorn M
Neuro-oncology advances ; 2022 Mar 01
Deciphering tumour tissue organization by 3D electron microscopy and machine learning.
de Senneville BD, Khoubai FZ, Bevilacqua M, Labedade A, Flosseau K, Chardot C, Branchereau S, Ripoche J, Cairo S, Gontier E, Grosset CF
Communications biology ; 2021 Dec 13
HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: focus on EBP50 and IRSp53.
Capdevielle C, Desplat A, Charpentier J, Sagliocco F, Thiebaud P, Thézé N, Fédou S, Hooks KB, Silvestri R, Guyonnet-Duperat V, Petrel M, Raymond AA, Dupuy JW, Grosset CF, Hagedorn M
Neuro-oncology ; 2020 Apr 15
Impact of Extracellular Matrix Components to Renal Cell Carcinoma Behavior.
Majo S, Courtois S, Souleyreau W, Bikfalvi A, Auguste P
Frontiers in oncology ; 2020 Apr 28
LIM Homeobox-2 Suppresses Hallmarks of Adult and Pediatric Liver Cancers by Inactivating MAPK/ERK and Wnt/Beta-Catenin Pathways.
Mosca N, Khoubai FZ, Fedou S, Carrillo-Reixach J, Caruso S, Del Rio-Alvarez A, Dubois E, Avignon C, Dugot-Senant N, Guettier C, Mussini C, Zucman-Rossi J, Armengol C, Thiébaud P, Veschambre P, Grosset CF
Liver cancer ; 2021 Dec 21


Partners

Team leaders

Christophe GROSSET
Research Director / DR


Team members

Aya ABOU HAMMOUD
Post PhD Researcher / Post-doc

Patrick AUGUSTE
Lecturer / MCU

Alexia CALOVOULOS
PhD Student / Doc

Hala FATROUNI
PhD Student / Doc

Christophe GROSSET
Research Director / DR

Guillaume HERRAULT
PhD Student / Doc

Pierre KLEIN
Engineer Assistant / AI

Aksam MERCHED
Professor / PU

Marina SIMON COMA
Post PhD Researcher / Post-doc

Camille TOCQUEVILLE
PhD Student / Doc

Philippe VESCHAMBRE
Lecturer / MCU