Project title: Epigenetic regulation of tumor metastasis in small intestinal neuroendocrine tumors (SI-NETs)

Return To Search

Project Description:

In this research project, Dr. Barazeghi will use advanced sequencing technologies in small intestinal neuroendocrine tumors (SI-NETs) to investigate the driver epigenetic mechanisms that occur in a primary tumor to make it metastatic. This knowledge will advance our understanding of the mechanisms underlying metastasis with the ultimate goal of improving prognostic factors for SI-NET metastasis and informing strategies to prevent metastases.

What critical NET problem will you try to solve through your research?

The key molecular mechanisms that contribute to metastatic progression in SI-NETs are not yet fully understood. Since these tumors are highly epigenetically dysregulated but have fewer genetic mutations, it is important to investigate epigenetic aberrations in multiple tumors from the same patient to identify specific genes and regulatory elements responsible for metastasis. 

Why is this important?

Most patients with SI-NETs already have distant metastases when diagnosed. This research project is focused on uncovering the reversible epigenetic changes that may be the key regulators of metastasis. This information could lead to the development of targeted therapies and improved predictions for SI-NET metastasis. 

What will you do as part of this research project?

In this project, Dr. Barazeghi and her team will combine a unique tumor biobank and advanced technologies, such as assays for transposase-accessible chromatin sequencing (ATAC-seq), to identify specific epigenetic targets associated with metastasis in SI-NETs. These potential targets will then be evaluated experimentally to discover new ways to treat and predict the spread of SI-NETs. 

How might your research improve the diagnosis and/or treatment of NETs? 

Identifying risk factors and biomarkers linked to metastatic potential may contribute to the development of preventive measures and screening tools for earlier detection and treatment of metastasis in SI-NETs. This knowledge could personalize treatment plans based on individual metastatic profiles, enhancing the chances of successful outcomes.

What is your next step?

The first step is to gain new knowledge about the underlying epigenetic events, regulatory elements, and specific genes involved in the metastatic progression of SI-NETs. As a next step, our specific findings will be further evaluated using a large independent validation cohort and other preclinical models to develop new strategies for impeding metastasis and for improving prognostic biomarkers.

Outcomes:

Epigenetic events regulate when and how genes are expressed without altering the underlying DNA sequence. The aim of this research project is to better understand how specific epigenetic alterations may drive the metastatic spread of small intestinal neuroendocrine tumors (SI-NETs). Many patients with this type of cancer already have metastases when they are diagnosed, but the biological reasons behind this spread are still poorly understood. By learning more about these mechanisms, our long-term goal is to help develop new treatments that could prevent or slow down the spread of the disease.

To address this, we analyzed tumor tissues from patients with multifocal SI-NETs, meaning patients who have several tumors in the small intestine at the same time. We collected both primary and metastatic tumors directly after surgery at the Uppsala University Hospital during 2024. These samples were analyzed using a technique that allows us to see which parts of the tumor DNA are active and may be controlling important cancer-related processes.

After optimizing the procedure, we successfully analyzed tumor samples from four patients. In total, 11 tumor samples passed all quality checks and were included in the final analyses. The sequencing data from these samples were carefully analyzed using a customized analysis pipeline developed together with bioinformatics experts. Our analyses identified over half a million regions in the DNA that showed activity and could be linked to gene regulation.

We found that about 25% of these active regions were located at gene promoters that regulate gene expression. When we compared primary tumors with metastatic tumors, we observed clear differences. Some DNA regions were more active in primary tumors, while many more were active in metastatic tumors. Further analysis showed that regions active in primary tumors were linked to processes involved in sensing and responding to signals, whereas regions active in metastatic tumors were mainly associated with cell division and the ability of cancer cells to attach and move, features that are important for cancer spread.

Currently, we are investigating the most promising findings from this analysis in laboratory experiments using well-established SI-NET cell models. These experiments help us test whether and how the identified genes influence cancer cell movement, which is a key step in metastasis. At the same time, we are validating our findings in a larger and independent group of SI-NET tumor samples from our biobank. This allows us to assess whether the identified genes are consistently important across many patients.

Overall, we believe that the results from this project significantly improve our understanding of how SI-NETs spread. The genes and mechanisms identified in this study provide a strong starting point for future research aimed at developing new treatments and, ultimately, improving outcomes for patients by preventing or limiting metastasis.

« Back to all funded research projects