Original Article a RTK-Based Functional Rnai Screen Reveals Determinants of PTX-3 Expression
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Targeting Synthetic Lethality Between the SRC Kinase and the EPHB6 Receptor May Benefit Cancer Treatment
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment James M. Paul1,*, Behzad Toosi2,*, Frederick S. Vizeacoumar2,*, Kalpana Kalyanasundaram Bhanumathy2, Yue Li3,4,5, Courtney Gerger2, Amr El Zawily2,6, Tanya Freywald7, Deborah H. Anderson7, Darrell Mousseau8, Rani Kanthan2, Zhaolei Zhang3,4, Franco J. Vizeacoumar2,7, Andrew Freywald2 1Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada 2Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada 3Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada 4The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada 5Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA 6Faculty of Science, Damanhour University, Damanhour, 22516, Egypt 7Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada 8Cell Signaling Laboratory, Neuroscience Cluster, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada *These authors contributed equally to this work Correspondence to: Franco J. Vizeacoumar, email: [email protected] Andrew Freywald, email: [email protected] Keywords: breast cancer, genetic interaction, synthetic lethality, EPHB6, SRC kinase Received: April 22, 2016 Accepted: June 17, 2016 Published: July 13, 2016 ABSTRACT Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. -
Patents Related to EPH Receptors and Ligands
NEWS & ANALYSIS discuss EPH receptor–ephrin signalling Patents related to EPH receptors and its role in disorders such as tumour and ligands growth and progression, nerve injury and inflammation, and highlight therapeutic EPH receptors are a family of receptor approaches that are currently under tyrosine kinases that, together with their investigation. Here in TABLE 1 we highlight ligands, are involved in cell positioning, patent applications published in the past tissue and organ patterning as well as the 3 years related to EPH receptors and ligands. control of cell survival. In their Review Data were researched using the Espacenet on page 39, Lackman and colleagues database. Table 1 | Recent patent applications related to EPH receptors and ligands Nature Reviews | Drug Discovery Publication Applicants Subject numbers NZ 581397 AstraZeneca Pyrimidine compounds that inhibit EPH receptors and are useful for treating cancer HK 1108702 Sanford-Burnham Peptides that selectively bind to EPH type-B receptors (EPHBs); useful for tumour imaging and the Institute treatment of neoplastic disease, neurological disease and vascular disease US 2013091591 California Institute of During angiogenesis, arterial cells express ephrin B2, and its receptor EPHB4 is expressed on venous Technology cells; this distinction can be used in methods to alter angiogenesis and to assess the effect of drugs WO 2013052710 Expression Pathology Selected reaction monitoring mass spectrometry-based and multiple reaction monitoring mass spectrometry-based assays for quantifying -
The Kinase Defective EPHB6 Receptor Tyrosine Kinase Activates MAP Kinase Signaling in Lung Adenocarcinoma
175-179.qxd 29/5/2009 01:21 ÌÌ ™ÂÏ›‰·175 INTERNATIONAL JOURNAL OF ONCOLOGY 35: 175-179, 2009 175 The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma JUN YU1,2, ETMAR BULK1, PING JI1, ANTJE HASCHER1, STEFFEN KOSCHMIEDER1, WOLFGANG E. BERDEL1 and CARSTEN MÜLLER-TIDOW1 1Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany; 2Department of Preclinical Experiment Center, Fourth Military Medical University, Xi'an, P.R. China Received January 28, 2009; Accepted March 13, 2009 DOI: 10.3892/ijo_00000326 Abstract. Decreased expression levels of EPHB6, a member Elk-1 (8,9). ERK1/2 are negatively regulated by a family of of the receptor tyrosine kinases (RTKs), are associated with dual-specificity (Thr/Tyr) MAPK phosphatases, known as an increased risk of metastasis development in early stage DUSPs or MKPs, and pharmacologically by MEK inhibitors non-small cell lung cancer (NSCLC). However, the signaling such as U0126 and PD98059 (10). properties of the kinase-defective EPHB6 receptor are not EPH receptors form the largest known subfamily of well-understood. Here, we show that expression of EPHB6 receptor tyrosine kinases, and to date, the EPH subfamily in A549 lung adenocarinoma cells led to phosphorylation of contains 16 members in vertebrates (11,12). The EPH receptors the MAP kinase ERK. Conversely, siRNA based knockdown interact with a family of ligands located on the surfaces of of EPHB6 reversed ERK phosphorylation. Intriguingly, adjacent cells, named Ephrins including Ephrin-As and EPHB6-induced phosphorylation of ERK was uncoupled Ephrin-Bs subgroups. The EPH receptors are also grouped by activation of the Elk-1 transcriptional factor. -
A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma
414 Original Article A Review of VEGF/VEGFR-Targeted Therapeutics for Recurrent Glioblastoma David A. Reardon, MDa,b; Scott Turner, MDc; Katherine B. Peters, MD, PhDc; Annick Desjardins, MDc; Sridharan Gururangan, MDa,b; John H. Sampson, MD, PhDa; Roger E. McLendon, MDd; James E. Herndon II, PhDe; Lee W. Jones, PhDf; John P. Kirkpatrick, MD, PhDf; Allan H. Friedman, MDa; James J. Vredenburgh, MDc; Darell D. Bigner, MD, PhDd; and Henry S. Friedman, MDa,b; Durham, North Carolina Key Words ability effect of VEGF inhibitors, the Radiologic Assessment in Neu- Glioblastoma, angiogenesis, vascular endothelial growth factor, ro-Oncology (RANO) criteria were recently implemented to bet- malignant glioma ter assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mech- Abstract anisms to VEGF inhibitors and identification of effective therapy Glioblastoma, the most common primary malignant brain tumor after bevacizumab progression are currently a critical need for pa- among adults, is a highly angiogenic and deadly tumor. Angiogen- tients with glioblastoma. (JNCCN 2011;9:414–427) esis in glioblastoma, driven by hypoxia-dependent and indepen- dent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encourag- ing rates of radiographic response and progression-free survival, Malignant gliomas, including the most common sub- and adequate safety, led the FDA to grant accelerated approval of type of glioblastoma, are rapidly growing destructive tu- bevacizumab, a humanized monoclonal antibody against VEGF, for mors that extensively invade locally but rarely metasta- the treatment of recurrent glioblastoma in May 2009. -
Ephb3 Suppresses Non-Small-Cell Lung Cancer Metastasis Via a PP2A/RACK1/Akt Signalling Complex
ARTICLE Received 7 Nov 2011 | Accepted 11 Jan 2012 | Published 7 Feb 2012 DOI: 10.1038/ncomms1675 EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex Guo Li1, Xiao-Dan Ji1, Hong Gao1, Jiang-Sha Zhao1, Jun-Feng Xu1, Zhi-Jian Sun1, Yue-Zhen Deng1, Shuo Shi1, Yu-Xiong Feng1, Yin-Qiu Zhu1, Tao Wang2, Jing-Jing Li1 & Dong Xie1 Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis. 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai 200031, China. 2 The Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200433, China. -
Profiling Data
Compound Name DiscoveRx Gene Symbol Entrez Gene Percent Compound Symbol Control Concentration (nM) JNK-IN-8 AAK1 AAK1 69 1000 JNK-IN-8 ABL1(E255K)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317I)-nonphosphorylated ABL1 87 1000 JNK-IN-8 ABL1(F317I)-phosphorylated ABL1 100 1000 JNK-IN-8 ABL1(F317L)-nonphosphorylated ABL1 65 1000 JNK-IN-8 ABL1(F317L)-phosphorylated ABL1 61 1000 JNK-IN-8 ABL1(H396P)-nonphosphorylated ABL1 42 1000 JNK-IN-8 ABL1(H396P)-phosphorylated ABL1 60 1000 JNK-IN-8 ABL1(M351T)-phosphorylated ABL1 81 1000 JNK-IN-8 ABL1(Q252H)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(Q252H)-phosphorylated ABL1 56 1000 JNK-IN-8 ABL1(T315I)-nonphosphorylated ABL1 100 1000 JNK-IN-8 ABL1(T315I)-phosphorylated ABL1 92 1000 JNK-IN-8 ABL1(Y253F)-phosphorylated ABL1 71 1000 JNK-IN-8 ABL1-nonphosphorylated ABL1 97 1000 JNK-IN-8 ABL1-phosphorylated ABL1 100 1000 JNK-IN-8 ABL2 ABL2 97 1000 JNK-IN-8 ACVR1 ACVR1 100 1000 JNK-IN-8 ACVR1B ACVR1B 88 1000 JNK-IN-8 ACVR2A ACVR2A 100 1000 JNK-IN-8 ACVR2B ACVR2B 100 1000 JNK-IN-8 ACVRL1 ACVRL1 96 1000 JNK-IN-8 ADCK3 CABC1 100 1000 JNK-IN-8 ADCK4 ADCK4 93 1000 JNK-IN-8 AKT1 AKT1 100 1000 JNK-IN-8 AKT2 AKT2 100 1000 JNK-IN-8 AKT3 AKT3 100 1000 JNK-IN-8 ALK ALK 85 1000 JNK-IN-8 AMPK-alpha1 PRKAA1 100 1000 JNK-IN-8 AMPK-alpha2 PRKAA2 84 1000 JNK-IN-8 ANKK1 ANKK1 75 1000 JNK-IN-8 ARK5 NUAK1 100 1000 JNK-IN-8 ASK1 MAP3K5 100 1000 JNK-IN-8 ASK2 MAP3K6 93 1000 JNK-IN-8 AURKA AURKA 100 1000 JNK-IN-8 AURKA AURKA 84 1000 JNK-IN-8 AURKB AURKB 83 1000 JNK-IN-8 AURKB AURKB 96 1000 JNK-IN-8 AURKC AURKC 95 1000 JNK-IN-8 -
Anti-Human EPHA4 / EPH Receptor A4 (Internal) Polyclonal Antibody
For Research Use Only. REV: 9/9/2014 Anti-Human EPHA4 / EPH Receptor A4 (Internal) Polyclonal Antibody CatalogID MC-2841 Target Protein EPH receptor A4 (EPHA4) Synonyms EPHA4 Antibody, CEK8 Antibody, EK8 Antibody, Ephrin type-A receptor 4 Antibody, HEK8 Antibody, SEK Antibody, TYRO1 Antibody, TYRO1 protein tyrosine kinase Antibody, Tyrosine-protein kinase TYRO1 Antibody, EPH receptor A4 Antibody, EPH-like kinase 8 Antibody Family / Subfamily Protein Kinase / Ephrin Receptor Host EPHA4 antibody was produced in Rabbit Clonality Polyclonal Immunogen Species EPHA4 / EPH Receptor A4 antibody was raised against Human Antigen Type Synthetic peptide Immunogen EPHA4 / EPH Receptor A4 antibody was raised against synthetic 18 amino acid peptide from internal region of human EPHA4. Percent identity with other species by BLAST analysis: Human, Gorilla, Gibbon, Monkey, Marmoset, Panda, Bovine, Dog, Bat, Horse, Pig (100%); Mouse, Rat, Hamster, Elephant, Rabbit, Opossum, Platypus, Xenopus (94%); Turkey, Chicken (89%); Lizard (83%). Specificity Human EPHA4. BLAST analysis of the peptide immunogen showed no homology with other human proteins. Epitope Internal Reactivity Human (human tissues have been tested in IHC with FFPE) Predicted Reactivity Gorilla, Gibbon, Monkey, Bat, Bovine, Dog, Horse, Pig, Mouse, Rat, Hamster, Rabbit, Xenopus Purification Immunoaffinity purified Presentation PBS, 0.1% sodium azide. Recommended Storage Long term: -70°C; Short term: +4°C Uses IHC - Paraffin (3 μg/ml) (Optimal dilution to be determined by the researcher) Size 50 µg Concentration 1 mg/ml For research use only. Not intended for human, diagnostic, therapeutic, or drug use. Immunohistochemistry Anti-EPHA4 antibody MC-2841 IHC of human kidney, glomerulus. Immunohistochemistry of formalin-fixed, paraffin- embedded tissue after heat-induced antigen retrieval. -
Epha3 Inhibits Migration and Invasion of Esophageal Cancer Cells by Activating the Mesenchymal‑Epithelial Transition Process
722 INTERNATIONAL JOURNAL OF ONCOLOGY 54: 722-732, 2019 EphA3 inhibits migration and invasion of esophageal cancer cells by activating the mesenchymal‑epithelial transition process XIA CHEN1,2, BIN LU2,3, QIAN MA2, CHENG-DONG JI4 and JIAN-ZHONG LI3 1Key Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090; 2International Joint Cancer Institute; 3Department of Biochemical Pharmacy, Second Military Medical University, Shanghai 200433; 4Department of Scientific Research Management, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, P.R. China Received June 13, 2018; Accepted November 2, 2018 DOI: 10.3892/ijo.2018.4639 Abstract. Eph receptor tyrosine kinases are critical for cell-cell Introduction communication during normal and oncogenic development. Eph receptor A3 (EphA3) expression is associated with Esophageal cancer is the eighth most prevalent type of tumor promotion in certain types of cancer; however, it acts cancer worldwide (1,2), of which, esophageal squamous cell as a tumor suppressor in others. The expression levels of carcinoma (ESCC) is a predominant histological type (3). EphA3 and its effects on tumor progression in esophageal Despite advances in diagnostic tools, surgical techniques and squamous cell carcinoma (ESCC) cell lines were determined chemotherapy over the past few decades, the 5-year survival using reverse transcription-quantitative polymerase chain rate for patients with esophageal cancer ranges between reaction analysis and a Transwell invasion assay. The present 15 and 20% (4). Therefore, novel diagnostic tools, therapeutic study demonstrated that EphA3 expression was decreased strategies and molecular prognostic markers are urgently in ESCC tissues and cell lines. Treatment with the DNA required for this disease. -
Recombinant Human Epha8 Fc Chimera Catalog Number: 6828-A8
Recombinant Human EphA8 Fc Chimera Catalog Number: 6828-A8 DESCRIPTION Source Mouse myeloma cell line, NS0derived Human EphA8 Human IgG (Glu31Thr542) IEGRMD 1 (Pro100Lys330) Accession # NP_065387 Nterminus Cterminus Nterminal Sequence Glu31 Analysis Structure / Form Disulfidelinked homodimer Predicted Molecular 83.2 kDa (monomer) Mass SPECIFICATIONS SDSPAGE 94 kDa, reducing conditions Activity Measured by its binding ability in a functional ELISA. When Recombinant Human EphA8 Fc Chimera is coated at 2 μg/mL (100 μL/well), the concentration of Biotinylayed Recombinant Human EphrinA5 Fc Chimera (Catalog # BT374) that produces 50% of the optimal binding response is 212 ng/mL. Endotoxin Level <0.01 EU per 1 μg of the protein by the LAL method. Purity >90%, by SDSPAGE under reducing conditions and visualized by silver stain. Formulation Supplied as a 0.2 μm filtered solution in MES, NaCl, PEG, CHAPS and Imidazole. See Certificate of Analysis for details. PREPARATION AND STORAGE Shipping The product is shipped with dry ice or equivalent. Upon receipt, store it immediately at the temperature recommended below. Stability & Storage Use a manual defrost freezer and avoid repeated freezethaw cycles. l 12 months from date of receipt, 70 °C as supplied. l 1 month, 2 to 8 °C under sterile conditions after opening. l 3 months, 20 to 70 °C under sterile conditions after opening. BACKGROUND EphA8, also known as Hek3 and Eek, is a 120 kDa glycosylated member of the Eph family of transmembrane receptor tyrosine kinases (1, 2). The A and B classes of Eph proteins are distinguished by Ephrin ligand binding preference but have a common structural organization. -
Structural and Functional Insights Into the Transmembrane Domain Association of Eph Receptors
International Journal of Molecular Sciences Review Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors Amita R. Sahoo 1 and Matthias Buck 1,2,3,4,* 1 Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; [email protected] 2 Department of Neurosciences, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA 3 Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA 4 Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA * Correspondence: [email protected] Abstract: Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding their mechanism of signal transduction across cellular membranes. We review the structural and functional aspects of EphA1/A2 association and the techniques used to investigate their TM domains: NMR, molecular modelling/dynamics simulations and fluorescence. We also introduce transmembrane peptides, which can be used to alter Eph receptor signaling and we provide a perspective for future studies. Citation: Sahoo, A.R.; Buck, M. Keywords: receptor tyrosine kinase (RTKs); Eph receptors; TM dimerization; transmembrane Structural and Functional Insights domain (TMD) into the Transmembrane Domain Association of Eph Receptors. Int. J. Mol. Sci. 2021, 22, 8593. https:// doi.org/10.3390/ijms22168593 1. The Family of Eph Receptors, Their Domain Structure and Function Erythropoietin-producing hepatocellular carcinoma receptors (Ephs) represent the Academic Editors: Dimitar B. -
Type of the Paper (Article
Table S1. Gene expression of pro-angiogenic factors in tumor lymph nodes of Ibtk+/+Eµ-myc and Ibtk+/-Eµ-myc mice. Fold p- Symbol Gene change value 0,007 Akt1 Thymoma viral proto-oncogene 1 1,8967 061 0,929 Ang Angiogenin, ribonuclease, RNase A family, 5 1,1159 481 0,000 Angpt1 Angiopoietin 1 4,3916 117 0,461 Angpt2 Angiopoietin 2 0,7478 625 0,258 Anpep Alanyl (membrane) aminopeptidase 1,1015 737 0,000 Bai1 Brain-specific angiogenesis inhibitor 1 4,0927 202 0,001 Ccl11 Chemokine (C-C motif) ligand 11 3,1381 149 0,000 Ccl2 Chemokine (C-C motif) ligand 2 2,8407 298 0,000 Cdh5 Cadherin 5 2,5849 744 0,000 Col18a1 Collagen, type XVIII, alpha 1 3,8568 388 0,003 Col4a3 Collagen, type IV, alpha 3 2,9031 327 0,000 Csf3 Colony stimulating factor 3 (granulocyte) 4,3332 258 0,693 Ctgf Connective tissue growth factor 1,0195 88 0,000 Cxcl1 Chemokine (C-X-C motif) ligand 1 2,67 21 0,067 Cxcl2 Chemokine (C-X-C motif) ligand 2 0,7507 631 0,000 Cxcl5 Chemokine (C-X-C motif) ligand 5 3,921 328 0,000 Edn1 Endothelin 1 3,9931 042 0,001 Efna1 Ephrin A1 1,6449 601 0,002 Efnb2 Ephrin B2 2,8858 042 0,000 Egf Epidermal growth factor 1,726 51 0,000 Eng Endoglin 0,2309 467 0,000 Epas1 Endothelial PAS domain protein 1 2,8421 764 0,000 Ephb4 Eph receptor B4 3,6334 035 V-erb-b2 erythroblastic leukemia viral oncogene homolog 2, 0,000 Erbb2 3,9377 neuro/glioblastoma derived oncogene homolog (avian) 024 0,000 F2 Coagulation factor II 3,8295 239 1 0,000 F3 Coagulation factor III 4,4195 293 0,002 Fgf1 Fibroblast growth factor 1 2,8198 748 0,000 Fgf2 Fibroblast growth factor -
Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
Author Manuscript Published OnlineFirst on March 29, 2019; DOI: 10.1158/1535-7163.MCT-18-0582 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Functional analysis of somatic mutations affecting receptor tyrosine kinase family in metastatic colorectal cancer Leslie Duplaquet1, Martin Figeac2, Frédéric Leprêtre2, Charline Frandemiche3,4, Céline Villenet2, Shéhérazade Sebda2, Nasrin Sarafan-Vasseur5, Mélanie Bénozène1, Audrey Vinchent1, Gautier Goormachtigh1, Laurence Wicquart6, Nathalie Rousseau3, Ludivine Beaussire5, Stéphanie Truant7, Pierre Michel8, Jean-Christophe Sabourin9, Françoise Galateau-Sallé10, Marie-Christine Copin1,6, Gérard Zalcman11, Yvan De Launoit1, Véronique Fafeur1 and David Tulasne1 1 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T – Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France. 2 Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, F-59000 Lille, France 3 TCBN - Tumorothèque Caen Basse-Normandie, F-14000 Caen, France. 4 Réseau Régional de Cancérologie – OncoBasseNormandie – F14000 Caen – France. 5 Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, F-76000 Rouen, France. 6 Tumorothèque du C2RC de Lille, F-59037 Lille, France. 7 Department of Digestive Surgery and Transplantation, CHU Lille, Univ Lille, 2 Avenue Oscar Lambret, 59037, Lille Cedex, France. 8 Department of hepato-gastroenterology, Rouen University Hospital, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, F-76000 Rouen, France. 9 Department of Pathology, Normandy University, INSERM 1245, Rouen University Hospital, F 76 000 Rouen, France. 10 Department of Pathology, MESOPATH-MESOBANK, Centre León Bérard, Lyon, France. 11 Thoracic Oncology Department, CIC1425/CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, Paris, France.