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Enteric Glial Cell Reprogramming by Loss of MENIN in Duodenopancreatic Neuroendocrine Tumors

Award Number: R01CA304024
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Enteric Glial Cell Reprogramming by Loss of MENIN in Duodenopancreatic Neuroendocrine Tumors - Individuals with the Multiple Endocrine Neoplasia I (MEN1) syndrome develop pituitary and duodenopancreatic neuroendocrine tumors (dpNETs), heterogenous malignancies whose cellular origins and etiology are poorly understood, limiting evidence-based treatment. Despite sharing morphological and functional similarities with neurons, dpNETs are thought to arise from mature enteroendocrine cells that differentiate from epithelial cell progenitors. The MEN1 locus encodes MENIN, a nuclear adaptor protein that regulates epigenomic processes like histone and subsequently DNA methylation. We deleted Men1 from neural crest-derived glial cells using the glial fibrillary associated protein (Gfap) promoter to drive Cre recombinase (GfapCre:Men1FL/FL), and found that NETs developed in the pituitary, small intestine and pancreas. However, tumors did not develop when Kif3a, a primary cilia protein that transduces Hedgehog (HH) signaling, was also deleted (GfapCre:Men1FL/FL: Kif3aFL/FL). This indicates that NETs can arise from a neural crest-derived cell (glial cell lineage); yet it is unknown how loss of MENIN function reprograms glial cells to acquire a neuroendocrine phenotype but likely involves epigenetic modifications and chromatin remodeling. Our objective is to define how loss of MENIN contributes to neuroendocrine tumorigenesis by allowing epigenetic modification of bivalent loci to increase enteric glial cell plasticity rendering them susceptible to Hedgehog (HH)-mediated reprogramming. MENIN tightly controls the expression of bivalent loci by recruiting lysine methyl transferases (KMT) and Polycomb Repressor Complex 2 (PRC2) that trimethylate histone 3 at lysine 4 (H3K4Me3) and lysine 27 (H3K27Me3) respectively. We hypothesize that disrupting MENIN function dampens glial cell specification by increasing the repressive histone methylation mark H3K27Me3 on bivalent loci, while inducing expression of HH signaling components that promotes neural specification and dpNET formation. Aim 1. Define how Men1 deletion in enteric glial cells contributes to dpNET development in vivo. Aim 2. Define how Men1 deletion (ΔMen1) epigenetically modulates glial-specifying genes. Aim 3. Define how HH signaling redirects enteric glial lineage after ΔMen1. Our approach uses primary enteric glial cultures from human biopsies and glial-deleted Men1 mice in tandem with proteinchromatin assays to define how loss of MENIN initiates chromatin remodeling and increases their susceptibility to extracellular signals like HH. Since it is unknown when and how the human tumors develop, mouse models are required to study the initiation of tumorigenesis. We will lineage trace enteric glial cell fate into ΔMen1-derived NETs using the tdTomato reporter with inducible glial-restricted Cre drivers and use single cell transcriptomics from enteric glial cell cultures to perform pseudotime trajectories. We will compare histone protein methylation in primary glial versus dpNET organoids (tumoroids) using protein-chromatin assays to define MENIN-regulated epigenetic reprogramming. We will use mouse and human neuroendocrine tumoroids to test the effect of HH inhibitors as modifiers of the epigenetic landscape to expand the repertoire of diagnostic/treatment approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $581,288 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Cause and Prevention Research	000	1	8/13/2026	NEW	$581,288
														Subtotal = $581,288

Grand Total All Awards = $581,288

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Enteric Glial Cell Reprogramming by Loss of MENIN in Duodenopancreatic Neuroendocrine Tumors

Award Number: R01CA304024

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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