Project title: Establishment and genome characterization of PNET mouse models

Description 

Pugh, together with Dr. Schramek and their colleagues, will build a genetically engineered mouse model that recapitulates the sequence of mutations as they are observed to develop in human pancreatic NETs. This model will enable the team to characterize the sequence of mutations that trigger genomic instability and allow for further molecular screening and drug development that will inform future patient studies.

What question will you try to answer through your research?

To improve our understanding of NET biology, cancers need to be reproduced in a model system that not only ensures faithful recapitulation of the tumor microenvironment with an intact immune system but also allows experimental manipulation and functional testing. We expect our models carrying a defined series of genetic alterations will allow us to uncover the underlying biology that triggers malignant progression and metastasis in pancreatic NETs.

Why is this important?

Mouse models of pancreatic NETs have been challenging to establish because of the step-wise nature of genetic mutation and the epigenetic alteration we recently discovered in this cancer. Our model will allow us to control when these mutations are introduced and then scan hundreds of genes to identify potential therapeutic targets that may arise over the course of cancer development. We expect these models to shed light on neuroendocrine tumor formation and immune biology, as well as serving as preclinical models to test new drug strategies targeting the unique series of genomic changes seen in these cancers.

What will you do as part of this research project?

We will establish a new genetically engineered mouse model that mirrors the sequence of mutations that arise during human pancreatic NET development. This model will be based on our pioneering work that mapped the distinct set and sequence of genetic changes that occur as human pancreatic NETs develop. We will confirm that the mouse tumors mimic those found in humans, and then use these models to identify the types of drugs that can disrupt the development and progression of pancreatic NETs.

How might your research improve the treatment of NETs?

Our goal is to repurpose existing drugs or develop new therapeutic molecules that may be used to treat pancreatic NETs. This project is a first step toward understanding the developmental biology and possible therapeutic targets that may arise in these cancers due to the striking and unique genomic configurations we observed during pancreatic NET development.

What is your next step?

The models we develop will serve as great tools for preclinical studies to test rational drug treatments and combinations. Once validated, we will return to human cell culture models, xenografts and patients to corroborate the biological relevance of our discoveries in humans.

Outcomes:

Pancreatic neuroendocrine tumors (PNETs) are a type of cancer that arises in the pancreas and can be very difficult to treat. We have found that PNETs develop through a series of genetic changes that cause the loss of more than half of the genetic material in the cells. This loss is associated with the cancer becoming more aggressive and spreading to other parts of the body. Within this research project, we have been trying to figure out how these tumors develop so that we can find new ways to treat them. One of the challenges in studying PNETs is that we don’t have a good animal model to test new treatments. We think that the reason for this is that we haven’t been able to introduce the right genetic changes in the right cells at the right time to mimic what happens in human PNETs.

We have now developed a special mouse that can develop PNETs just like humans do. This mouse has the same genetic changes that we see in human PNETs, and we can control when these changes happen. However, to our surprise, these mice did not develop tumors despite the fact that we engineered the same mutations as seen in human patients. We speculated that the failure to develop tumors might be routed in the fact that mouse chromosomes are different than human chromosomes – they are almost 10 times longer and that makes them much more stable. We further speculated that artificially shortening the mouse telomeres to a length similar to humans might trigger tumor development. Indeed, when we destroyed a gene responsible in maintaining chromosome ends in mice, we observed that our experimental mice developed neuroendocrine tumors in the pancreas.

In the future, this will allow us to study how the cancer develops, which genes trigger malignant progression and test new treatments at different stages of the disease. This work is important because it will help us find new ways to treat PNETs and other cancers that have similar genetic changes. We can use this mouse model to look for new drugs that could be used to treat these cancers and to understand the best time to use these drugs.

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