Spatial transcriptomics profiling of small intestine adenocarcinoma and adenoma in humans and a murine model with KRAS and loss of CDKN2a-p16

Authors

• Tyler D. Seckar, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Elena V. Komissarova, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Jing Sun, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Narine N. Le Fevre, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Zhong Ye, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Tristan Jordan, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Aylar Babaei, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Armando Del Portillo, Department of Pathology and Cell Biology, Columbia University, New York, NY.
• Jorge L. Sepulveda, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
• Antonia R. Sepulveda, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC. Electronic address: asepulveda@email.gwu.edu.

Document Type

Journal Article

Publication Date

2-26-2026

Journal

The American journal of pathology

DOI

10.1016/j.ajpath.2026.01.013

Keywords

Small bowel adenocarcinoma; Small intestine adenocarcinoma; extra-ampullary (non-ampullary) duodenal adenocarcinoma; mouse model small intestine cancer; spatial transcriptomics

Abstract

Small intestine adenocarcinomas (SIAC) in humans occur predominantly as extra-ampullary SIAC (SIAC/EDA), demonstrate intestinal-type or gastric-type differentiation and arise from precursor adenomas. The aims of this study were to determine spatial transcriptomics of SIAC/EDA differentiation subtypes and driver molecular pathways in humans and novel mouse models. Spatial transcriptomics and immunohistochemistry were performed in human and murine SIAC/EDA and adenomas. Mice with Cdkn2a/p16 conditional knockout, Kras expression, or both (p16KOKrasG12D) targeting LGR5 cell progenitors were generated, and histologic alterations were examined. Spatial transcriptomics identified differentiation signatures of intestinal and gastric-type SIAC/EDA and adenomas, their microenvironment, cell-cell signaling interactions driving neoplasia progression, and susceptibility to targeted therapies. Activated signaling pathways were not specific to differentiation subtype. Algorithm-inferred susceptibility to MEK inhibitors correlated with activation of MEK pathways in gastric-type SIAC. P16KOKrasG12D mice developed small intestine/duodenal adenomas by 11-15 months (10/14, 83%), and adenocarcinomas by 12-19 months, in contrast to wild-type mice (p=.0003). Spatial transcriptomics of mouse lesions largely replicated human SIAC/EDA differentiation signatures and signaling pathways. A novel genetically engineered mouse model that mimics gastric-type and intestinal-type adenomas and gastric-type SIAC/EDA is reported. Spatial transcriptomics provided a detailed understanding of cellular differentiation lineages, cancer microenvironment related to SIAC subtypes and driving pathways that may be leveraged to identify new molecular tools for pathologic diagnosis and potential targets for precision cancer therapies.

APA Citation

Seckar, Tyler D.; Komissarova, Elena V.; Sun, Jing; Le Fevre, Narine N.; Ye, Zhong; Jordan, Tristan; Babaei, Aylar; Del Portillo, Armando; Sepulveda, Jorge L.; and Sepulveda, Antonia R., "Spatial transcriptomics profiling of small intestine adenocarcinoma and adenoma in humans and a murine model with KRAS and loss of CDKN2a-p16" (2026). GW Authored Works. Paper 8661.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8661

Department

Pathology