New paper in Gastroenterology & our Liver Cancer Cell Lines Database

The last work of Sandra Rebouissou group is newly accepted for publication in Gastroenterology.

Entitled, “Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response” it is the first study to provide a comprehensive molecular characterization of most widely used liver cancer cell lines. All the data are available at : www.lccl.zucmanlab.com

Article available on Gastroenterology website.

 

 

 

 

New Publication in Nature Communications from Didier Jean group

Yuna Blum, from Ligue National Contre le Cancer and Didier Jean group used a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of malignant mesothelioma.

 

Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both onhistology and molecular profiling. Histology addresses inter-tumor and intra-tumor hetero-geneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, acombination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show thatmolecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to areconsideration of MPM molecular classifications. We show that each tumor can bedecomposed as a combination of epithelioid-like and sarcomatoid-like components whoseproportions are highly associated with the prognosis. Moreover, we show that this moresubtle way of characterizing MPM heterogeneity provides a better understanding of theunderlying oncogenic pathways and the related epigenetic regulation and immune andstromal contexts. We discuss the implications of thesefindings for guiding therapeuticstrategies, particularly immunotherapies and targeted therapies.

 

 

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New Publication in Nature Communications from Eric Letouzé bioinformatical group

Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress

We are proud to share you our last publication in Nature Communications. Quentin Bayard from Eric Letouzé group identifies a new hepatocellular carcinoma subclass with a rearrangement signature of replication stress and defined by Cyclin A2/E1 activation.

 

Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early- replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.

 

You can access to the full text on this link

New Publication of the lab in Int J Cancer about PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases.

Jie Yang, PhD student in the lab just published a work in International Journal of Cancer.

Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3-rs738409, TM6SF2-rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16-2.40], p = 0.005; OR = 1.45 [CI95%:1.08-1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4-rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52-6.06], p = 1.14E-09; OR = 1.79 [CI95%:1.25-2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22-3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3-rs738409 and TM6SF2-rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.

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New publication by Didier Jean team in Lung Cancer

Didier Jean team have just published a new paper in Lung Cancer. In this work the investigated anti-tumor effect of eight major signaling pathways inhibitors involved in malignant pleural mesothelioma (MPM) carcinogenesis. They found that three inhibitors were more efficient than cisplatin, the drug used as first-line chemotherapy in patients with MPM: verteporfin, a putative YAP inhibitor, defactinib, a FAK inhibitor and NSC668394, an Ezrin inhibitor.

Verteporfin, the most efficient inhibitor, induced cell proliferation arrest and cell death, and is effective on 3D spheroid multicellular model. Verteporfin sensitivity was YAP-independent and related to molecular classification of the tumors. Biomarkers based on gene expression were identified to predict accurately sensitivity to these three inhibitors.

Link to the publication