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Francoz S.,Experimental Oncology Group | Mathiaux J.,University of Bordeaux 1 | Dubus P.,University of Bordeaux 1 | Dubus P.,Bordeaux University Hospital Center
Bulletin du Cancer | Year: 2012

The high incidence and poor prognosis of lung cancer represent a major health problem. Currently, about 20% of lung cancer patients can benefit from targeted therapy after identification of EGFR, ALK or HER2 somatic mutations or rearrangements. Other mutations, such as KRas oncogenic mutation, are still orphans of validated targeted therapy. In this review, we describe the different mouse models of lung carcinoma. We then illustrate the interests of such models for the identification and validation of new therapeutic targets, for the study of secondary resistance and for their use as preclinical models and for new therapeutic strategy tests. © John Libbey Eurotext. Source


Lopez-Contreras A.J.,Genomic Instability Group | Lopez-Contreras A.J.,Copenhagen University | Specks J.,Genomic Instability Group | Barlow J.H.,U.S. National Institutes of Health | And 9 more authors.
Genes and Development | Year: 2015

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2TG) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity. © 2015 Lopez-Contreras et al. Source


Martinez-Bosch N.,Hospital del Mar Medical Research Institute IMIM | Iglesias M.,Hospital Del Mar | Munne-Collado J.,Hospital Del Mar | Martinez-Caceres C.,Fundacion Formacion Investigacion Sanitaria Region Murcia FFIS | And 6 more authors.
Journal of Pathology | Year: 2014

Pancreatic cancer has a dismal prognosis and is currently the fourth leading cause of cancer-related death in developed countries. The inhibition of poly(ADP-ribose) polymerase-1 (Parp-1), the major protein responsible for poly(ADP-ribosy)lation in response to DNA damage, has emerged as a promising treatment for several tumour types. Here we aimed to elucidate the involvement of Parp-1 in pancreatic tumour progression. We assessed Parp-1 protein expression in normal, preneoplastic and pancreatic tumour samples from humans and from K-Ras- and c-myc-driven mouse models of pancreatic cancer. Parp-1 was highly expressed in acinar cells in normal and cancer tissues. In contrast, ductal cells expressed very low or undetectable levels of this protein, both in a normal and in a tumour context. The Parp-1 expression pattern was similar in human and mouse samples, thereby validating the use of animal models for further studies. To determine the in vivo effects of Parp-1 depletion on pancreatic cancer progression, Ela-myc-driven pancreatic tumour development was analysed in a Parp-1 knock-out background. Loss of Parp-1 resulted in increased tumour necrosis and decreased proliferation, apoptosis and angiogenesis. Interestingly, Ela-myc:Parp-1-/- mice displayed fewer ductal tumours than their Ela-myc:Parp-1+/+ counterparts, suggesting that Parp-1 participates in promoting acinar-to-ductal metaplasia, a key event in pancreatic cancer initiation. Moreover, impaired macrophage recruitment can be responsible for the ADM blockade found in the Ela-myc:Parp-1-/- mice. Finally, molecular analysis revealed that Parp-1 modulates ADM downstream of the Stat3-MMP7 axis and is also involved in transcriptional up-regulation of the MDM2, VEGFR1 and MMP28 cancer-related genes. In conclusion, the expression pattern of Parp-1 in normal and cancer tissue and the in vivo functional effects of Parp-1 depletion point to a novel role for this protein in pancreatic carcinogenesis and shed light into the clinical use of Parp-1 inhibitors. Copyright © 2014 Pathological Society of Great Britain and Ireland. Source


Monasor A.,Genomic Instability Group | Murga M.,Genomic Instability Group | Lopez-Contreras A.J.,Genomic Instability Group | Navas C.,Experimental Oncology Group | And 3 more authors.
Cell Cycle | Year: 2013

Replication stress (RS) is a source of DNA damage that has been linked to cancer and aging, which is suppressed by the ATR kinase. In mice, reduced ATR levels in a model of the ATR-Seckel syndrome lead to RS and accelerated aging. Similarly, ATR-Seckel embryonic fibroblasts (MEF) accumulate RS and undergo cellular senescence. We previously showed that senescence of ATR-Seckel MEF cannot be rescued by p53-deletion. Here, we show that the genetic ablation of the INK4a/ Arf locus fully rescues senescence on ATR mutant MEF, but also that induced by other conditions that generate RS such as low doses of hydroxyurea or ATR inhibitors. In addition, we show that a persistent exposure to RS leads to increased levels of INK4a/Arf products, revealing that INK4a/ARF behaves as a bona fide RS checkpoint. Our data reveal an unknown role for INK4a/ARF in limiting the expansion of cells suffering from persistent replication stress, linking this well-known tumor suppressor to the maintenance of genomic integrity. © 2013 Landes Bioscience. Source


Martinelli P.,Epithelial Carcinogenesis Group | Madriles F.,Epithelial Carcinogenesis Group | Canamero M.,Comparative Pathology Unit | Carrillo-De Santa Pau E.,Epithelial Carcinogenesis Group | And 4 more authors.
Gut | Year: 2016

Background and aims: Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinarductal metaplasia, which is considered an initial step of mutant KRas-driven carcinogenesis. Therefore, the Gata6-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis. Design: We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of KRasG12V-driven tumours Results We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to KRasG12V, thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of KRasG12V-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic Gata6-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR. Conclusions: We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways. Source

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