Impact of innervation in pancreatic neuroendocrine tumor

Active Project Grant Awarded Last action

Award ID
F31CA314099
Recipient
Awarding agency
Obligated
$72,916

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date 0% complete
Originally
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Pancreatic neuroendocrine tumors (PNETS) are rare tumors derived from the highly innervated endocrine cells of the pancreatic islets. About 15% of PNETS exhibit perineural invasion (PNI), a histopathological finding wherein cancer cells envelop or invade peripheral nerves. As in other cancers, PNI in pnet is associated with vascular invasion, metastasis, recurrence, and worse overall survival. Previous studies have identified an aggressive metastasis-like primary subtype of pnet expressing genes related to neurogenesis. My single-cell transcriptomic study of pnet patient samples also identified a cancer cell state with upregulation of genes related to neuronal development (under review). However, the mechanisms underlying tumor-nerve crosstalk and potential neuronal mimicry in pnet are poorly understood. In this study, I will elucidate how pnet cancer cells interact with nerves in the tumor microenvironment (TME). The overarching goal of this proposed work is to test the hypothesis that tumor-nerve crosstalk alters immune/stromal composition, antitumor immunity, and malignant cell state and invasive potential in the microenvironment to promote cancer progression. I will test this hypothesis with two aims that leverage my labs' expertise in cancer neuroscience, spatial oncology, computational analysis, and a growing biobank of >40 human pnet resection specimens. In aim 1, I will characterize how nerves impact the immune microenvironment and antitumor response. I will perform single-cell spatial proteotranscriptomics (>1000 plex RNA, >40 plex protein) on PNETS from our biobank with and without PNI. I will compare differences in cell state and neighborhood cell type composition between these two groups and I will identify paracrine and juxtacrine interactions between cancer cells and nerves that may mediate PNI using an optimal transport algorithm. Next, I will examine how nerve injury affects macrophage phenotype and T cell responses by performing cocultures of siinfekl-expressing cancer cells, OT-1 T cells, and raw 264.7 macrophages. I will perform flow cytometry to assess T cell activation and exhaustion markers and live cell imaging to track cancer cell killing. In aim 2, I will use pnet cell lines to identify candidate genes that promote tropism towards nerves by performing a serial selection assay and identifying differentially expressed genes in cancer cells that are most tropic towards nerves. Next, I will engineer fluorescent crispr- activated cell lines of candidate genes to explore how these perturbations impact migration speed, extent of invasion, and neurite outgrowth with live cell imaging. By studying this poorly understood aspect of the TME, we endeavor to identify therapeutic targets that disrupt tumor-nerve crosstalk to improve patient outcomes in pnet.

Transactions

Action Obligated Date
Amendment $36,458
Amendment $0
Original award $36,458

Quick answers

Who received award F31CA314099?

F31CA314099 was awarded to President And Fellows Of Harvard College by National Cancer Institute (National Institutes of Health) on December 1, 2026.

How much is award F31CA314099 worth?

$72,916 has been obligated on F31CA314099.

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