Project title: Epigenetic dysregulation of transposons in pancreatic neuroendocrine tumors

Description 

Senapati is researching whether defects in the ATRX and DAXX genes activate certain sequences in DNA that cause pancreatic NETs to form. She is also studying changes in DNA methylation to find elements that may be activated in the formation of tumors. 

What question will you try to answer through your research?

My study will address which genetic components, called retrotransposons, are expressed in pancreatic NETs (PNETs) that have mutations in the ATRX and DAXX genes, and whether an abnormal expression of retrotransposon proteins can help predict outcomes for patients. My team and I will also explore how the ATRX/DAXX mutation in PNETs leads to dysregulation of retrotransposons that are silenced and tightly regulated in normal cells.

Why is this important?

ATRX/DAXX mutations in PNETs are associated with a worse prognosis for patients. If we better understand which retrotransposons are abnormally regulated in PNETs and how they lead to cancer progression, we may be able to identify markers that may affect prognosis and develop new treatment strategies for PNETs.

What will you do as part of this research project?

We will analyze the abnormal genomes of PNETs and the aberrant regulation of their genetic components that contribute to the formation of PNETs. We will explore the role and contribution of the ATRX and DAXX genetic mutations in causing pancreatic NETs. 

How might your research improve the treatment of NETs?

This study will help us identify genes and genetic pathways that may be used to develop diagnostic or prognostic markers and immunotherapeutic strategies to target PNETs. 

What is your next step?

Our study will explore whether the expression of retrotransposon proteins is associated with poorer clinical outcomes. The results may point to possible therapeutic strategies that target these proteins in PNETs.

Outcomes:

Pancreatic Neuroendocrine tumors (PNETs) are the second most common cancer of the pancreas. These tumors are often found in people that have a defect (or mutation) in MEN1, ATRX or DAXX genes that were inherited from parents or occurred during their lifetime. Studies in mouse models that were designed to mirror the human mutation of the MEN1 gene have shed some light on the possible role of this gene in tumor formation. However, the role of ATRX and DAXX mutation in tumor development is not clear. Studies in mouse have shown that ATRX and DAXX are responsible for suppressing harmful sequences in our DNA that are called transposable elements. These harmful sequences came from viral infections that happened millions of years ago, while humans were still evolving. The viral DNA inserted themselves into our DNA, and they can multiply themselves and cause mutations unless they are contained. The ATRX and DAXX genes and DNA methylation are part of the machinery that suppresses them. Changes in DNA methylation due to defects in the ATRX, DAXX, and MEN1 genes can lead to loss of suppression of these viral DNA sequences.

The research project aimed to explain whether defects in ATRX and DAXX will lead to activation of these viral sequences and whether this is bad for PNETs. In the course of the project, I was able to demonstrate that there is activation of retroviral elements in PNET tumors. Moreover, by comparing the genetic mutation of ATRX, DAXX and MEN1 in those tumors, I was able to show that ATRX and DAXX knockout leads to activation of specific types of retroviral DNA. In addition, I was able to make ATRX and DAXX knockout cells to model what happens in the PNETs with loss of function mutation of ATRX and DAXX. The study for the first time demonstrates that there is expression of retroviral DNA in PNET tumors. I also identified the types of retroviral DNA expressed and that ATRX and DAXX mutation may lead to expression of specific types of retroviral DNA. This knowledge can be taken forward to ask whether there are any specific retroviral DNA derived proteins on the tumor cell surface that can help in detection and targeting of these tumor cells.

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