Highly Resolved Spatial Mapping of Pancreatic Neuroendocrine Tumors for Intratumor and Intertumor Variability
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are the second most common malignancy of the pancreas. While considered a rare disease that currently affects 1 per 100,000 individuals annually, the incidence and prevalence of this tumor type has risen dramatically in recent decades. Notably, these tumors remain understudied and are challenging to treat due to their unpredictable biological behavior. For example, while some patients with this disease present with a slowly growing tumor, others develop an aggressive tumor that ultimately leads to widely metastatic disease. New biomarkers that can help predict which patients may develop a metastasis have been identified and validated in recent years; however, these biomarkers only capture the alterations in the cancer cells, while not fully appreciating the role played by the stromal and immune cells next to the tumor (i.e., tumor microenvironment). We propose that PanNET progression and aggressiveness is linked with important patient-specific factors found within this tumor microenvironment. Thus, the objective of this proposal is to use a state-of-the-art technology to comprehensively profile human tumors at the single cell level to accurately map different tumor subgroups and explore their underlying biology. Using MERFISH (multiplexed error-robust fluorescence in situ hybridization) technology, we aim to uncover the differences in the tumor microenvironment across 40 archived human tumors. As an example, by profiling the immune and stromal cell populations next to the tumor, we may uncover complex interactions that create an immunosuppressive microenvironment causing lack of response to emerging immuno-oncology therapies, which unfortunately are commonly observed in patients with rare disease. We will push the boundaries by incorporating innovative approaches at the technological, experimental, and computational level. This proposal directly addresses the fiscal year 2022 Rare Cancer Research Program Focus Area of identifying disease-defining molecular pathways, cell context, and microenvironment. Uncovering these complex interactions in the tumor microenvironment may lead to more accurately predicting which patients diagnosed with a PanNET will or will not eventually develop metastases. Additionally, over the next couple of years, these studies have the potential to directly lead to improved prediction capability for how patients might respond to a certain treatment (e.g., immunotherapy strategies). Finally, the results from this study will help provide a strong foundation for future therapeutic development of novel approaches for targeting PanNETs. Overall, potential new vulnerabilities in PanNETs can be discovered and this framework may provide the framework to execute similar projects in both PanNETs and other rare cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310671
Entities
People
- Christopher M Heaphy
Organizations
- Boston Medical Center
- United States Army