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Peer-reviewedCC BY 4.0The Journal of Clinical Investigation

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

  • Julie Karam1,2
  • Samantha E. Hoffman1,2,3
  • Amanda Garza1,2
  • Dan Gui1,2
  • Hannah I. Hoffman1,2,3
  • Breanna M. Titchen1,2,4
  • Yutaro Tanaka2,5
  • Erica Pimenta1,2
  • Theodora Pappa1,2,6
  • Laura Valderrabano1,2
  • Kevin Bi1,2
  • Riaz Gillani2,5,7
6 more authors
  • Lauren Brais1,2
  • Erin Shannon1,2
  • Jason L. Hornick1,8
  • Jihye Park1,2
  • Jennifer Chan1
  • Eliezer M. Van Allen1,2
8 affiliations
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  2. 2Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  3. 3Harvard/MIT MD-PhD Program, Boston, Massachusetts, USA.
  4. 4Division of Medical Sciences PhD Program in Biological and Biomedical Sciences, Harvard University, Cambridge, Massachusetts, USA.
  5. 5Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  6. 6Division of Endocrinology, Diabetes and Metabolism, Mass General Brigham, Boston, Massachusetts, USA.
  7. 7Division of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA.
  8. 8Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.
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Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic 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 2 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 profibrotic and proangiogenic 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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Cite

BibTeXRIS
BibTeX
@article{karam2026conserved,
  title = {{Conserved neuronal-like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors}},
  author = {Julie Karam and Samantha E. Hoffman and Amanda Garza and Dan Gui and Hannah I. Hoffman and Breanna M. Titchen and Yutaro Tanaka and Erica Pimenta and Theodora Pappa and Laura Valderrabano and Kevin Bi and Riaz Gillani and Lauren Brais and Erin Shannon and Jason L. Hornick and Jihye Park and Jennifer Chan and Eliezer M. Van Allen},
  journal = {The Journal of Clinical Investigation},
  year = {2026},
  month = sep,
  doi = {10.1172/jci204119},
  url = {https://doi.org/10.1172/jci204119},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Conserved neuronal-like and secretory programs define the spatial architecture of gastroenteropancreatic neuroendocrine tumors
AU  - Julie Karam
AU  - Samantha E. Hoffman
AU  - Amanda Garza
AU  - Dan Gui
AU  - Hannah I. Hoffman
AU  - Breanna M. Titchen
AU  - Yutaro Tanaka
AU  - Erica Pimenta
AU  - Theodora Pappa
AU  - Laura Valderrabano
AU  - Kevin Bi
AU  - Riaz Gillani
AU  - Lauren Brais
AU  - Erin Shannon
AU  - Jason L. Hornick
AU  - Jihye Park
AU  - Jennifer Chan
AU  - Eliezer M. Van Allen
PY  - 2026
DA  - 2026/09/01
JO  - The Journal of Clinical Investigation
DO  - 10.1172/jci204119
UR  - https://doi.org/10.1172/jci204119
AB  - Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic 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 2 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 profibrotic and proangiogenic 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.
SN  - 0021-9738
SN  - 1558-8238
ER  -