Conserved neuronal-like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors

Julie Karam; Samantha E. Hoffman; Amanda Garza; Dan Gui; Hannah I. Hoffman; Breanna M. Titchen; Yutaro Tanaka; Erica Pimenta; Theodora Pappa; Laura Valderrabano; Kevin Bi; Riaz Gillani; Lauren Brais; Erin Shannon; Jason L. Hornick; Jihye Park; Jennifer Chan; Eliezer M. Van Allen

doi:10.1172/JCI204119

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

Find articles by Park, J. in: PubMed | Google Scholar

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America

²Broad Institute of Harvard and MIT, Cambridge, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI204119.
Copyright © 2026, Karam et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 1, 2026 - Version history

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (PanNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program, and a secretory neuroendocrine program. Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in PanNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that neuronal-like-high regions localized to densely cellular tumor areas with relative depletion of stromal infiltration, whereas secretory neuroendocrine-high regions occupied fibrovascular and stromal niches enriched for endothelial, fibroblast, and myeloid populations, and associated with TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enriched for pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

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Conserved neuronal-like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors

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