The goal of this research proposal lies squarely within the mission of the Neuroendocrine Tumor Research Foundation to fund research to discover cures and more effective treatments for carcinoid, pancreatic, and related neuroendocrine cancers. This proposal seeks to understand mechanisms leading to neoplasm formation and oncogenic transformation for this poorly understood class of tumors. Specifically, we aim to understand the role of ATRX/DAXX/H3.3-mediated chromatin dysregulation in pancreatic neuroendocrine tumors. These studies will identify important mechanisms of genome regulation, potentially transforming our understanding of neuroendocrine tumors with a goal towards the development of new diagnostic markers and possible new methods of intervention.
Alterations in epigenetic regulation of the genome are commonly observed in human cancers, with many chromatin remodeling complexes displaying an unexpectedly high mutation rate resulting in their deletion or inactivation in specific tumor types. Recently, inactivating mutations to the ATRX or DAXX genes were identified in 43% of pancreatic neuroendocrine tumors (panNETs). ATRX/DAXX are known to chaperone the histone variant H3.3 to repetitive regions including telomeres, and tumors harboring these mutations undergo telomere dysfunction resulting in alternative lengthening of telomeres, or ALT. These observations have resulted in intense study of the role of ATRX/DAXX/H3.3 in the ALT phenotype, but many questions remain. We still do not know (1) the molecular details of how ATRX/DAXX is recruited to target loci, (2) the functional relevance of H3.3 incorporation at these regions, and (3) whether misregulation of H3.3 deposition plays a role in ALT that may drive the development of panNETs. The long-term objective of these studies is to achieve a better understanding of the mechanisms by which ATRX/DAXX influences chromatin function to regulate biological outcomes. Our broad hypothesis is that ATRX/DAXX-mediated deposition of H3.3 protects chromosome integrity at repetitive regions, including telomeres and endogenous retroviral elements (ERVs). Our study will explore the molecular mechanisms of chromatin assembly at these regions, and determine the specific role of chromatin dysregulation in panNETs.
NET Research Foundation
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