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.

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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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).

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

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