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The role of Daxx in initiation and progression of pancreatic neuroendocrine tumors

English title The role of Daxx in initiation and progression of pancreatic neuroendocrine tumors
Applicant Perren Aurel
Number 144236
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.12.2012 - 31.03.2016
Approved amount 395'391.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Clinical Cancer Research

Keywords (4)

Chromosomal instability; Daxx; ALT; Endocrine pancreatic tumors (pNETs)

Lay Summary (German)

Lead
Wir nehmen an, dass sich aus dem Mutationsspektrum in humanen pancreatischen neuroendokrinen Tumoren (pNET) verschiedene therapeutisch relevante Untergruppen definieren lassen. DAXX/ATRX Mutationen wurden vor kurzem in einem grossen Teil von pNET beschrieben. Die Mechanismen, wie diese Mutationen zu pNET führen, sind weitgehend unbekannt. Wir Untersuchen deshalb die Auswirkungen von DAXX Mutationen in pNET Zell-Linien, einem transgenen Mausmodell und in operierten humanen pNET.
Lay summary

Die Rolle von Daxx in Entstehung und Progression von neuroendokrinen Pankreastumoren

 Sporadische pNET können Mutationen in unterschiedlichen Genen aufweisen; vor kurzem wurden Mutationen in den DAXX und ATRX Genen in 25% und 18% sporadischer pNET gefunden. Somit handelt es sich hierbei um die häufigsten genetischen Veränderungen dieser Tumoren. Die daraus resultierenden Veränderungen führen über einen neuen und noch wenig bekannten Mechanismus der Tumorentstehung. pNET mit DAXX oder ATRX Mutationen zeigen Telomere mit sehr unterschiedlicher Länge, auf Grund der Aktivierung eines Telomerase unabhängigen Mechanismus, ALT (Alternative Lengthening of Telomeres) genannt. Dieser Mechanismus wird bei pNET ohne Mutation in einem dieser 2 Gene nicht gefunden. Klinisch scheinen DAXX und ATRX mutierte Tumoren eine gute Prognose aufzuweisen, aber dies muss sich in weiteren Studien bestätigen.

Wir gehen davon aus, dass diese DAXX/ATRX mutierten pNET einen spezifischen Subtypen darstellen, der charakteristische molekulare und klinische Charakteristika aufweist. Im laufenden Projekt untersuchen wir die Rolle von Daxx in der Entstehung und Progression von pNET an unterschiedlichen Modellen: Wir untersuchen an menschlichen Tumoren molekulare und klinische Veränderungen, welche bei Daxx oder Atrx- Protein-Verlust auftreten. Wir untersuchen die Effekte von Daxx Über- und Unterexpression in pNET Zellinien. Wir werden zusätzlich eine Maus generieren, bei welcher Daxx in pankreatischen Beta-Zellen entfernt wird (konditionelle Daxx- knock out Maus) um in diesem in-vivo-Modell die Entstehung von endokrinen Pankreastumoren zu erreichen und zu untersuchen. Diese Studie wird zum besseren Verständnis der Entstehung von pNET führen, einschliesslich der Mechanismen, welche zu ALT führen. Ein Maus-Modell mit pNET, welches der menschlichen Situation gleichen würde, wäre auch ein wichtiges Werkzeug, um präklinische Therapie-Studien durchzuführen.

Direct link to Lay Summary Last update: 01.11.2012

Responsible applicant and co-applicants

Employees

Publications

Publication
Genetic and epigenetic drivers of neuroendocrine tumours (NET)
Di Domenico Annunziata, Wiedmer Tabea, Marinoni Ilaria, Perren Aurel (2017), Genetic and epigenetic drivers of neuroendocrine tumours (NET), in ENDOCRINE-RELATED CANCER, 24(9), 315-334.
Hypo-methylation mediates chromosomal instability in pancreatic NET.
Marinoni I, Wiederkeher A, Wiedmer T, Pantasis S, Di Domenico A, Frank R, Vassella E, Schmitt A, Perren A (2017), Hypo-methylation mediates chromosomal instability in pancreatic NET., in Endocrine-related cancer, 24(3), 137-146.
Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors.
Marinoni Ilaria, Kurrer Anja Schmitt, Vassella Erik, Dettmer Matthias, Rudolph Thomas, Banz Vanessa, Hunger Fabio, Pasquinelli Silvan, Speel Ernst-Jan, Perren Aurel (2014), Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors., in Gastroenterology, 146(2), 453.
Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms.
Schmitt Anja Maria, Pavel Marianne, Rudolph Thomas, Dawson Heather, Blank Annika, Komminoth Paul, Vassella Erik, Perren Aurel (2014), Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms., in Neuroendocrinology, 100(1), 35-44.

Collaboration

Group / person Country
Types of collaboration
Chissie Thirlwell, UCL Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Marianne Pavel, Charite Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
E-J Speel, University Mastricht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ENETS 2016 Individual talk Overview - Profiling in GEP NET 10.03.2016 Barcelona, Spain Perren Aurel;
ENETS 2016 Talk given at a conference Epigenetic remodeling upon DAXX and ATRX loss in pancreatic Neuro-endocrine tumor (pNETs). 09.03.2016 Barcelona, Spain Perren Aurel; Marinoni Ilaria;
ENETS 2015 Poster Significance of ATRX/DAXX Expression and Alternative Lengthening of Telomeres in Insulinomas and Neuroendocrine Tumors of Small Intestine 10.03.2015 Barcelona, Spain Perren Aurel;
ESMO Preceptorship on GI neuroendocrine tumors (NETs) Individual talk Future outlook for NEN: The pathologists point of view 29.11.2014 Leuven, Belgium Perren Aurel;
World MEN Individual talk Indication for surgery in MEN1 neuroendocrine pancreatic tumors: Biology 25.09.2014 Vienna, Austria Perren Aurel;
26th European Congress of Pathology ESP Individual talk Do tumorigenic and signalling pathways go the same route? 30.08.2014 London, Great Britain and Northern Ireland Perren Aurel;
Renaten Paris, NocTurNEs: What's new in the field of NET Individual talk  La perte des gènes DAXX et ATRX est associée à une instabilité chromosomiques et réduit la survie des patients atteints de TNE GEP 03.07.2014 Paris, France Perren Aurel;
USCAP 2014 Talk given at a conference DAXX and/or ATRX Loss Defines Chromosomal Instability and Poor Outcome in Pancreatic NET 11.03.2014 San Diego, United States of America Marinoni Ilaria; Krebs Philippe; Perren Aurel;
ENETS 2014 Individual talk What's new in my field 07.03.2014 Barcelona, Spain Perren Aurel;
ENETS post graduate course Individual talk Pathology 04.03.2014 Barcelona, Spain Perren Aurel;
DKG Berlin Talk given at a conference NET, es sind nicht alle gleich 20.02.2014 Berlin, Germany Perren Aurel;
Scientific NEN exchange Talk given at a conference DAXX/ATRX loss in pNET 30.01.2014 Berlin, Germany Perren Aurel; Marinoni Ilaria;
European Society of Pathologgy meeting Talk given at a conference Prognostic and predictive role of MGMT immunoreactivity and promoter methylation in sporadic pancreatic endocrine neoplasms 01.09.2013 Lissabon, Portugal Marinoni Ilaria; Perren Aurel;
ENETS 2013 Talk given at a conference DAXX and/or ATRX Loss Defines Chromosomal Instability and Poor Outcome in Pancreatic NET 07.03.2013 Barcelona, Spain Perren Aurel; Marinoni Ilaria;


Awards

Title Year
Second price for best oral presentation, ENETS 2016 2016
Hakan Ahlman Award for best publication of the year "DAXX and ATRX Loss Defines Chromosomal Instability and Poor Outcome in Pancreatic NET", awarded by the European Neuroendocrine Tumor Society in Barcelona 2015
Second price for best oral presentation, ENETS 2014 2014

Associated projects

Number Title Start Funding scheme
108257 Genetik endokriner Pankreastumoren: Protein-, RNA- und Mutationsanalyse von Kandidatengenen 01.04.2005 Project funding (Div. I-III)
164484 Epigenetic reprogramming in the progression of pancreatic Neuro-Endocrine Tumors 01.04.2016 Marie Heim-Voegtlin grants
188639 Metabolic changes in early and late progression steps of pancreatic neuroendocrine tumors 01.08.2020 Project funding (Div. I-III)

Abstract

The role of Daxx in initiation and progression of pancreatic neuroendocrine tumors (Zusammenfassung des Forschungsplans)Background: The molecular etiology of pancreatic neuroendocrine endocrine tumors (pNETs) is still largely unknown and very few animal models resembling the human situation are available. Recently, DAXX/ATRX mutations have been identified in 45% of sporadic pNET. Associations of these mutations with alternative lengthening of telomeres (ALT) and with good clinical outcome have been described by others. Yet there is a strong association between ALT and chromosomal instability in other tumor types. In pNET patients we have shown a strong association of chromosomal instability with adverse prognosis in previous SNSF projects. Furthermore, our preliminary results suggest that Daxx loss is associated with early pNETs relapse, thereby challenging what has been reported so far. An animal model reflecting the most frequent human situation of Daxx/Atrx negative tumors is critically missing, that would be suitable for studying the mechanism of tumorigenesis and provide a tool for pre-clinical studies.Working hypothesis: We hypothesize that: 1. DAXX and ATRX are tumor suppressor genes in endocrine cells, and that loss of either Daxx or Atrx may be involved in initiation and/or progression of pNETs. 2. DAXX/ATRX mutated pNETs represent a genetically defined subgroup of pNETs and DAXX mutations can be a model for this subgroup. 3. DAXX mutations are associated with Daxx protein loss, ALT, chromosomal instability and adverse outcome. Specific aims: i) Assessment of whether DAXX mutation/deletion in pancreatic endocrine cells is an initiating or a late event in tumorigenesis. ii) Evaluation of differences between pNETs with Daxx loss and other types of pNETs regarding ALT, chromosomal instability and prognosis, iii) Generation of a murine model of Daxx induced pNET to reflect the most frequent human situation of DAXX/ATRX mutated tumors. Experimental design: To achieve the above mentioned goals, experiments will be performed: on human samples, on pNET cell lines and on Daxx knock-out mice. i. Daxx in initiation and/or progression: Daxx expression and ALT activation will be analyzed in pre-neoplastic and neoplastic lesions of MEN1 patients. The effects of DAXX overexpression versus siRNA knock-down on apoptosis will be studied in pNET cell lines. ii. Characterization of DAXX/ATRX mutated pNETs: Analysis of the correlation of Daxx/Atrx loss and ALT activation with data on chromosomal instability and survival in 120 pNET samples. iii. (i/ii) Generation of a beta cell specific Daxx conditional knock out mouse: Evaluation of tumor formation, isolation of murine Daxx(-/-) beta cells, crossing of the mice with Men1(+/-) strain, that spontaneously develop tumors of endocrine organs.Expected value of the proposed project: The clarification of the role of Daxx loss in pNET tumorigenesis will allow a better understanding of the etiology of these tumors, which is a prerequisite for the development of new therapeutic targets. A similar transformation mechanism may apply for other tumors with similar mutations such as glioblastomas. Additionally, dissection of the mechanisms underlying ALT activation will help to design treatment strategies in other tumor types, especially sarcomas, where therapeutic options are currently very scarce.
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