Project title: Role of the peripheral nervous system in pancreatic neuroendocrine tumors

Description

What critical problem/question will researchers try to answer?
The microenvironment of neuroendocrine tumors plays an important role in cancer progression and clinical outcomes. The role of nerves in neuroendocrine tumors is not well understood even though tumor innervation and invasion of cancer cells into nerves has been associated with worse patient prognosis in multiple studies. In this project, we will study tumor-nerve interactions in pancreatic neuroendocrine tumors (PNETs) to deepen our understanding of the mechanisms by which these interactions may promote disease progression in PNETs.

Why is this important?
Approximately 15% of PNETs exhibit cancer cell invasion of nerves (also known as perineural invasion), which has been associated with reduced patient survival and increased cancer-associated pain. The contribution of the nervous system to the development and progression of PNETs is an understudied area of research in neuroendocrine tumors. We hypothesize that tumor-nerve crosstalk alters cancer cell state and invasive potential, as well as the anti-tumor immune response, to promote cancer progression.

What will the researchers do?
In this project, we will use state-of-the-art spatial biology methods to characterize the distribution and abundance of nerve subtypes in the PNET microenvironment using a large and growing biobank of patient-derived PNET tumors. Furthermore, we will use a computational technique recently published called Spatially-Constrained Optimal Transport Interaction Analysis (SCOTIA) to identify interactions between cancer cells and nerves that may play a role in promoting nerve growth, cancer cell invasion of nerves, and immune cell modulation. Finally, we will use advanced genetically engineered cell line models to validate how candidate genes influence these cancer-nerve interactions and change the properties of the cancer cells and other non-malignant cells in the tumor microenvironment.

How might this improve treatment of neuroendocrine cancer?
By studying this poorly understood aspect of the neuroendocrine tumor microenvironment, we hope to identify new therapeutic targets that disrupt tumor-nerve crosstalk to ultimately lead to the development of a novel class of “neurotherapies” to improve patient outcomes.

What is the next step?
After the successful completion of this project, we anticipate having a shortlist of targets involved in deleterious cancer-nerve interactions in PNET. The next step will be further validation in animal models and screening for drugs that target these interactions. Ultimately, we hope that we can develop clinical trials to test the effectiveness of these new “neurotherapy” agents.

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