Project title: Defining the Multicellular Ecosystem of Nonmetastatic & Metastatic PanNETs

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Description

The goal of Dr. Singhi’s pilot project grant is to characterize gene expression changes that occur in pancreatic neuroendocrine tumors as they metastasize to other organs. The project’s two-phase approach will not only evaluate the tumor but also the surrounding tumor microenvironment.  

What critical NET problem/question will researchers try to answer?

Dr. Singhi and his colleagues believe their proposal will lead to the identification of specific gene expression changes that can predict the prognosis of a pancreatic neuroendocrine tumor and potential targets for treatment. 

Why is this important?

Pancreatic neuroendocrine tumors are the second most common pancreatic malignancy and are increasing in prevalence. The 5-year survival of patients who have these neoplasms is highly dependent on the metastatic spread to other organs. Identifying markers that can predict metastasis is therefore of utmost importance. Moreover, these markers may represent potential targets to improve the care for these patients.

What will the researchers do?

The study conducted by Dr. Singhi and his research team involves a two-phased approach. The first is an analysis discovery phase of 120 patient specimens. The second phase of the study will involve a validation cohort of 338 patient specimens where near single-cell analysis will be performed to identify markers of prognosis and potential treatment.

How might this improve treatment of NETs?

The wealth of knowledge gained through the research team’s approach is expected to lead to a comprehensive characterization of pancreatic neuroendocrine tumors with a focus on identifying specific differences between metastatic and non-metastatic neoplasms. These differences have the potential to represent novel targets for future treatments. 

What is the next step?

The next steps of our study will be to validate our findings in a prospective fashion in a CLIA/CAP accredited laboratory as a clinical test to improve patient care.

Outcomes:

Pancreatic neuroendocrine tumors, often called PanNETs, are a varied group of cancers that arise from the hormone-producing islet cells within the pancreas. These tumors exhibit a wide spectrum of clinical behavior; some are slow-growing and indolent, while others can be highly aggressive with a tendency to metastasize. To better understand the genetic drivers of these tumors, this research proposal utilized whole transcriptome sequencing (WTS) of 224 patients from University of Pittsburgh Medical Center, Cedars Sinai, New York University, Utrecht University, and Johns Hopkins. WTS analyzes all the RNA in a tumor, providing a comprehensive snapshot of which genes are active and revealing structural abnormalities like fusion genes, where two separate genes have broken and incorrectly joined together. The primary goal of this research was to identify new biomarkers within PanNETs that could more accurately predict a tumor’s aggressiveness and help guide patient treatment. Initial study findings were the discovery of recurrent BEND2 fusion genes in a small but distinct subgroup of highly aggressive PanNETs. These fusions, primarily CHD7::BEND2 and EWSR1::BEND2, were found exclusively in a cluster of tumors characterized by adverse features, including high histologic grade and universal metastasis at the time of diagnosis or during follow-up. These tumors were also more likely to occur in younger, female patients.

The clinical implications of this discovery are substantial. The presence of the BEND2 fusion protein, which can be detected using a standard laboratory test called immunohistochemistry, was identified as a powerful and independent predictor of poor patient outcomes. Patients whose tumors expressed BEND2 had significantly shorter disease-free and disease-specific survival compared to those without the marker. Notably, the presence of a BEND2 fusion gene was mutually exclusive with other well-known mutations in PanNETs, such as those in the ATRX and DAXX genes, suggesting it represents a distinct and alternative pathway for tumor progression. This study identifies BEND2 fusion genes as a novel oncogenic mechanism responsible for a particularly aggressive subtype of pancreatic neuroendocrine tumors. This work makes a significant contribution to cancer research by expanding our understanding of the molecular pathways, particularly those involving chromatin remodeling, that drive PanNET metastasis. For future cancer patients, this research paves the way for more personalized medicine. Incorporating BEND2 testing alongside existing markers like ATRX and DAXX can provide a more accurate risk profile for a patient’s tumor. This improved risk stratification will better equip clinicians to make critical treatment decisions, such as recommending immediate surgical intervention versus an active surveillance approach, ultimately helping to tailor therapy and improve patient outcomes.

Current ongoing studies with this data are the additional identification of TBL1X fusion genes and the characterization of PanNETs arising from 5 cell lineages: alpha, beta, delta, epsilon, and PP cells. Interestingly, ALT-positive PanNETs arise from alpha cells, BEND2 fusion positive cases in delta cells, and TBL1X in delta cells. Epsilon derived PanNETs were also identified as an aggressive subgroup of PanNETs. We are actively identifying driver genes in this subset of PanNETs.

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