TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup

Le Panel européen : une source statistique longitudinale sur les revenus et les conditions de vie des ménages

Articuler un numéro spécial d'Économie et Statistique autour d'une source statistique(et non d'un thème) peut paraître surprenant et peu conforme aux habitudes édito-riales de la revue. Plusieurs raisons ont pourtant poussé à le faire dans le cas du Panel européen. En premier lieu, le lecteur aura un aperçu de la richesse des études empiriques rendues possibles par un panel de ménages combinant l'étude de plusieurs thèmes. En second lieu - et également en raison des nombreuses possibilités d'exploitations qu'il offrait - le Panel européen a été largement diffusé au sein de l'Insee ainsi qu'à d'autres organismes. Ce numéro peut être considéré comme l'aboutissement du groupe de travail qui a réuni périodiquement depuis 1998 des chercheurs de tous horizons.Ansieau Dominique, Breuil, Hourriez Jean-Michel. Le Panel européen : une source statistique longitudinale sur les revenus et les conditions de vie des ménages. In: Economie et statistique, n°349-350, 2001. Le panel européen : une nouvelle source statistique sur les ménages. pp. 3-15

Le Panel européen : une source statistique longitudinale sur les revenus et les conditions de vie des ménages

[fre] Articuler un numéro spécial d'Économie et Statistique autour d'une source statistique(et non d'un thème) peut paraître surprenant et peu conforme aux habitudes édito-riales de la revue. Plusieurs raisons ont pourtant poussé à le faire dans le cas du Panel européen. En premier lieu, le lecteur aura un aperçu de la richesse des études empiriques rendues possibles par un panel de ménages combinant l'étude de plusieurs thèmes. En second lieu - et également en raison des nombreuses possibilités d'exploitations qu'il offrait - le Panel européen a été largement diffusé au sein de l'Insee ainsi qu'à d'autres organismes. Ce numéro peut être considéré comme l'aboutissement du groupe de travail qui a réuni périodiquement depuis 1998 des chercheurs de tous horizons.

Intestinal Epithelial Cells Adapt to Chronic Inflammation through Partial Genetic Reprogramming

Reactive oxygen species (ROS) are considered to be the main drivers of inflammatory bowel disease. We investigated whether this permanent insult compels intestinal stem cells to develop strategies to dampen the deleterious effects of ROS. As an adverse effect, this adaptation process may increase their tolerance to oncogenic insults and facilitate their neoplastic transformation. We submitted immortalized human colonic epithelial cells to either a mimic of chronic inflammation or to a chemical peroxide, analyzed how they adapted to stress, and addressed the biological relevance of these observations in databases. We demonstrated that cells adapt to chronic-inflammation-associated oxidative stress in vitro through a partial genetic reprogramming. Through a gene set enrichment analysis, we showed that this program is recurrently active in the intestinal mucosae of Crohn’s and ulcerative colitis disease patients and evolves alongside disease progression. Based on a previously reported characterization of intestinal stem and precursor cells using tracing experiments, we lastly confirmed the activation of the program in intestinal precursor cells during murine colorectal cancer development. This adaptive process is thus likely to play a role in the progression of Crohn’s and ulcerative disease, and potentially in the initiation of colorectal cancer

National prospective study on the use of local haemostatic agents during partial nephrectomy

International audienceOBJECTIVE:To assess the use of local haemostatic agents (HAs) in a prospective multicentre large series of partial nephrectomies (PNs).PATIENTS AND METHODS:Prospective National Observational Registry on the Practices of Haemostasis in Partial Nephrectomy (NEPHRON): the study was conducted in 54 French urological centres from 1 June to 31 December 2010. In all, 570 consecutive patients undergoing a PN were enrolled in this study in a prospective manner. The data was collected prospectively via an electronic case-report form: five different sheets were included for preoperative, perioperative, postoperative and follow-up data respectively. Information related to haemostasis was analysed.RESULTS:The median patient age was 60 years and the mean (range) tumour size was 3.68 (0.19-15) cm. An HA was primarily used in 71.4% of patients, with a statistically significant difference among surgical approaches (P = 0.024). In 91.8% of cases, a single use of a HA was sufficient for achieving haemostasis. The HA was used either alone (13.9%) or in association with sutures (80.3%). One or more additional haemostatic action(s) was needed in 12.3% of the cases. When comparing patients who received a HA with those who did not receive a HA, there was no statistical difference between the groups for tumour size (P = 0.542), collecting system drainage (P = 0.538), hospital stay (P = 0.508), operation time (P = 0.169), blood loss (P = 0.387) or transfusion rate (P = 0.713).CONCLUSION:HAs are widely used by urologists during PN. Progress is needed for standardising HA application, especially for the timing of application. For the time being, the role of the HA in nephron-sparing surgery is still to be evaluated

The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context

International audienceNutrient availability is a key determinant of tumor cell behavior. While nutrient‐rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non‐derepressible 2 (GCN2; also known as eIF‐2‐alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53‐mediated apoptosis in patient‐derived models of colon adenocarcinoma (COAD). In nutrient‐rich conditions, a cell‐autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl‐tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2–MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first‐line chemotherapy oxaliplatin, on patient‐derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co‐inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells

EGF induces EMT only in cells with <i>EGFR</i> mutation and <i>TWIST1</i> expression.

<p>EGFR mutated human lung cancer cell lines (H1975, H1650, HCC827) were treated with EGF. <b>A.</b> Cell morphology obtained by phase-contrast microscopy. <b>B. </b><i>TWIST1</i>, <i>CDH2</i>, <i>VIM</i>, <i>CDH1</i> and <i>JUP</i> expression as assessed by quantitative RT-PCR. mRNA levels are expressed relative to the untreated control condition. Each column represents the mean ±SD of 3 independent experiments each one done in triplicate.</p

Expression of <i>TWIST1</i>, mesenchymal (<i>CDH2</i>, <i>VIM</i>, <i>SNAI1</i>, <i>ZEB1</i>) and epithelial (<i>CDH1</i>, <i>JUP</i>) markers in lung adenocarcinoma cell lines.

<p>Assessment of <i>TWIST1</i>, <i>CDH2</i> (N-Cadherin), <i>VIM</i> (Vimentin), <i>SNAI1 (SNAIL1)</i>, <i>ZEB1</i>, <i>CDH1</i> (E-Cadherin) and <i>JUP (plakoglobin)</i> transcriptional expression by quantitative RT-PCR. The relative expression levels between samples were calculated using the comparative delta Ct (threshold cycle number). In each run, in addition to study samples, normal human lung RNA was used as calibrator. Each value represents the mean ±SD of three independent experiments each one run in triplicate.</p

TWIST1 expression in tumor samples.

<p><b>A.</b> Assessment of <i>TWIST1</i> expression by quantitative RT-PCR in <i>EGFR</i> mutated (M) and wild type (WT) tumors assessed by quantitative RT-PCR. <b>B.</b> Representative microphotographs (10×) of immunohistochemical expression of TWIST1 in primary <i>EGFR</i> mutated human lung tumors (sample 230 (1), sample 55 (2), sample 288 (3)) or wild type tumors (sample 149 (4)). Arrows point out cells for which staining is positive. TWIST1 positive staining is seen for samples 2 and 3 in cytoplasm and nucleus.</p

Basal expression of EMT markers in cell lines.

<p><b>A.</b> Assessment of TWIST1, Vimentin, N-Cadherin, E-Cadherin and Plakoglobin showing qualitative expression of markers by western blotting. <b>B.</b> Representative photomicrographs of TWIST1 expression in <i>EGFR</i> mutated cell lines (H1650 and HCC827) and in H1299 as assessed by immunofluorescence.</p