Project title: Understanding the tumor suppressor activities of ATRX-DAXX through epigenomic profiling and animal models

Objective

To create models to understand the role of ATRX and DAXX in neuroendocrine tumor development with the ultimate goal of developing new therapies for patients by targeting these processes and to establish the precise changes in chromosome structure resulting from mutations in ATRX and DAXX.

The chromosomes in our cells are composed of equal amounts of DNA and protein. The cellular machine of ATRX-Daxx helps to build and maintain chromosome structure at specific sites in our genome, including telomeres, the special structures that cap and protect the ends of our chromosomes.

Previous CFCF-funded researchers discovered mutations in the genes ATRX and Daxx among tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these exciting and promising findings, the precise role of ATRX and Daxx in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed.

Dr. Lewis began working on this project alongside Dr. C. David Allis at The Rockefeller University.  Then Dr. Lewis established his own lab at the University of Wisconsin-Madison.(This grant was first awarded to C. David Allis, PhD, The Rockefeller University)

Dr. Lewis’ team will conduct experiments and create models to understand the role of ATRX and Daxx in neuroendocrine tumor development with the ultimate goal of developing new therapies for patients by targeting these processes. Furthermore, they will establish the precise changes in chromosome structure resulting from mutations in ATRX and DAXX. Knowledge of these changes could shed light on not only neuroendocrine cancers but many other cancer types as well.

Research Objectives

1. Transcriptome and epigenomic analyses of pancreatic neuroendocrine tumor subtypes
2. Faithfully recapitulate pancreatic neuroendocrine tumor initiation and progression through conditional deletion of ATRX and Daxx tumor suppressors

Abstract

In this research project ,Dr. Lewis and his team will conduct a set of experiments to understand 1) why pancreatic neuroendocrine cells that lack ATRX-Daxx are more likely to become tumor cells and 2) how ATRX-DAXX act as tumor suppressors in pancreatic neuroendocrine cells.

Specifically, they will focus on understanding how chromosome structure and the turning on and off of genes change when pancreatic neuroendocrine cells lack ATRX-Daxx. Results from these studies will identify new molecular targets for novel treatments for neuroendocrine tumor patients.

This project will: identify new molecular targets for neuroendocrine tumor treatment, diagnosis and prognosis; generate mouse models to test new, targeted therapies for patients; and determine how mutations in ATRX and Daxx affect chromosome structure in neuroendocrine tumors.

Publication

Chan CS, Laddha SV, Lewis PW, Koletsky MS, Robzyk K, Da Silva E, Torres PJ, Untch BR, Li J, Bose P, Chan TA, Klimstra DS, Allis CD, Tang LH.  ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Nat Communications. 2018;9(1):4158. Published 2018 Oct 12. doi:10.1038/s41467-018-06498-2

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