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