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Epigenetic reprogramming in the progression of pancreatic Neuro-Endocrine Tumors

Applicant Marinoni Ilaria
Number 164484
Funding scheme Marie Heim-Voegtlin grants
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Cancer Research
Start/End 01.04.2016 - 31.03.2018
Approved amount 205'196.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Molecular Biology

Keywords (4)

Alternative Lenghtening of Telomeres; Pancreatic Neuro-Endocrine tumors; Epigenetics; DAXX/ATRX

Lay Summary (Italian)

Lead
I tumori pancreatici neuroendocrini (pNET) rappresentano il 3% delle neoplasie pancreatiche. Attualmente non esistono trattamenti risolutivi per questo tipo di malattia e l’unica cura possibile resta la resezione chirurgica che però purtroppo non sempre è possibile, specialmente per i tumori in stadio avanzato. I meccanismi molecolari responsabili della formazione e dello sviluppo dei pNETs non sono ancora conosciuti. La metilazione del DNA è un’importante modificazione che regola sia l’espressione dei geni che la stabilità del genoma; per questo motivo può avere un grosso impatto sullo sviluppo dei tumori. Molto poco è noto sullo stato di metilazione del DNA nei pNET. Con questo progetto intendiamo delineare specifici profili di metilazione del DNA di distinti gruppi di pNET e identificare potenziali target e molecole coinvolte nello sviluppo e nella crescita di questi tumori.
Lay summary

Recentemente in 40% dei pNET sporadici sono state identificate mutazioni nei geni che codificano per le proteine DAXX e ATRX. Abbiamo precedentemente dimostrato che pNET con queste mutazioni sono particolarmente aggressivi e maligni. Inoltre, abbiamo osservato che tumori mutati in DAXX e ATRX mostrano instabilità del genoma, che è un meccanismo spesso coinvolto nella crescita e nella selezione di cloni aggressivi. DAXX e ATRX regolano la metilazione del DNA interagendo con gli enzimi responsabili di questa modificazione (DNMTR1-3). Dati preliminari indicano che in tumori mutati per DAXX o ATRX il DNA è ipo-metilato rispetto agli altri tumori.

La mia ipotesi è che mutazioni in DAXX o ATRX inducano un cambiamento nel profilo di metilazione del DNA il quale determina un alterato profilo di espressione dei geni e instabilità del genoma. Entrambi questi fattori determinano la crescita e lo sviluppo di questo particolare gruppo di pNET.

Nello specifico una volta identificato lo stato di metilazione del DNA nei tumori negativi per DAXX e ATRX, questi risultati verranno integrati con il profilo di espressione del RNA degli stessi campioni. In questo modo sarà possibile identificare geni e molecole di RNA diversamente espresse in maniera dipendente dalla metilazione del DNA. Una volta identificati questi targets cellule primarie di pNET isolate da pazienti verranno trattate con diversi trattamenti anti-tumorali già in uso in clinica o che specificatamente inibiscano la funzione dei targets selezionati.

Questo progetto contribuirà a comprendere quali sono i meccanismi molecolari che innescano la formazione e la crescita di pNET e a identificare potenziali nuove specifiche terapie per pNET con mutazioni in DAXX e ATRX.

Direct link to Lay Summary Last update: 01.02.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Genomic landscape in gastroenteropancreatic neuroendocrine neoplasms and its usefulness in improving the prognostic evaluation
Marinoni Ilaria, Schmitt Anja, Di Domenico Annunziata (2018), Genomic landscape in gastroenteropancreatic neuroendocrine neoplasms and its usefulness in improving the prognostic evaluation, in Diagnostic Histopathology, 111.
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, 315.
Hypo-methylation mediates chromosomal instability in pancreatic NET.
Wiederkeher Astrid, Wiedmer Tabea, Pantasis Sophia, Di Domenico Annunziata, Vassella Erik, Schmitt Anja, Perren Aurel (2017), Hypo-methylation mediates chromosomal instability in pancreatic NET., in Endocrine Related Cancer, 137-146.
New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies
Schmitt Anja, Marinoni Ilaria, Blank Annika, Perren Aurel (2016), New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies, in Endocrine Pathology, 33.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
15th Annual Conference of European Neuro-Endocrine Tumor Society Talk given at a conference Epigenetic changes in DAXX and/or ATRX negative pancreatic Neuro-Endocrine tumors 08.03.2018 Barcelona, Spain Marinoni Ilaria;
14th Annual Conference of European Neuro-Endocrine Tumor Society Talk given at a conference 3D primary cells culture: a new promising pre-clinical model for pancreatic Neuro-endocrine tumors (pNETs) 08.03.2017 Barcelona, Spain Marinoni Ilaria;
Invited Seminar Individual talk Progression and Malignancy of pNETs: morphology meets molecular biology 04.11.2016 London, University College, Great Britain and Northern Ireland Marinoni Ilaria;
Spanish group of Neuro-endocrine tumors (GETNE) XII GETNE International Symposium Talk given at a conference Epigenetic Dysregulation in Neuro-endocrine Tumors. 29.09.2016 Barcelona, Spain Marinoni Ilaria;


Awards

Title Year
First prize for the best oral Basic Science Abstract at the 15th Annual Conference of European Neuro-Endocrine Tumor Society. 8-9 March, Barcelona, Spain. Epigenetic changes in DAXX and/or ATRX negative pancreatic Neuro-Endocrine tumors (Presenter: Di Domenico A., PhD student working on the project under my supervision). 2018
Second prize for best Oral Basic Science Abstract 14th Annual Conference of European Neuro-Endocrine Tumor Society. 8-10 March 2017 Barcelona, Spain. 3D primary cells culture: a new promising pre-clinical model for pancreatic Neuro-endocrine tumors (pNETs). 2017

Associated projects

Number Title Start Funding scheme
144236 The role of Daxx in initiation and progression of pancreatic neuroendocrine tumors 01.12.2012 Project funding (Div. I-III)

Abstract

Underlying mechanisms of Pancreatic Neuro-Endocrine tumors (pNETs) formation are still elusive and currently there is no means to pre-select patients for specific treatment based on gene mutations or pathways activation. Cancer cells are characterized by a complex interplay between genetic and epigenetic abnormalities that drive the evolution of the malignancy. Epigenetic influences not only gene expression but also telomeres function as well as genomic stability. Epigenetic of pNETs is poorly understood. Mutations in DAXX (Death associated protein 6) or ATRX (ATR-X gene) with correspondent loss of proteins expression occur in 40% of pNETs. DAXX and ATRX negative tumors show ALT (Alternative Lengthening Telomeres) activation a mechanism for telomeres length maintenance, telomerase independent. We have recently shown that loss of DAXX or ATRX predicts for poor disease outcome and that DAXX/ATRX negative tumors show chromosomal instability. DAXX and ATRX regulate the epigenetic status of the cells by mediating both chromatin structure organization and DNA methylation. Preliminary results obtained in our group indicate that DAXX/ATRX negative tumors show a lower level of global DNA methylation compared to positive ones. I hypothesize that DAXX/ATRX loss in pNETs induces an epigenetic reprogramming affecting gene expression as well as telomeres functions and genomic instability. These epigenetic abnormalities may drive the evolution of this subtype of tumors. In the current proposal I aim to: 1. Describe a specific epigenetic profile of DAXX/ATRX negative and ALT positive tumors2. Identify epigenetically regulated players of DAXX/ATRX negative pNETs development and validate their expression 3. Assess the capacity of the identified candidates to mediate response to anti-tumoral treatment. DNA-methylation arrays will be performed on 50 pNET human samples. Methylation profiles will be integrated with gene, miRNA and LncRNA expression data obtained on 30 samples respectively by gene expression arrays and Nanostring technology. Expression of interesting candidates found to be dysregulated from the comparative analysis will be validated on additional samples by Immunohistochemiestry, qRT-PCR and RNA in situ hybridization. Primary cells derived from pNET patients will be treated with different drugs currently in use for pNETs treatment as well as DNA demethylating agents and when possible with drugs targeting the new identified dysregulated pathways. This project will shed light into pancreatic neuro-endocrine tumorigeneisis mechanisms and may lead to the identification of new important therapeutic options.
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