Comparative single-cell transcriptomics of orthotopic and subcutaneous gastric tumors reveal immune and stromal heterogeneity
Year: 2025
Type: preprint
Abstract: Preclinical cancer models often use subcutaneous (SC) implantation, which fails to recapitulate the native tumor microenvironment (TME) of orthotopic (ORT) sites. To resolve these differences, we used single-cell RNA sequencing (scRNA-seq) on paired SC and ORT implants of the CKP syngeneic gastric cancer model. Histopathological differences were minimal, but scRNA-seq revealed profound TME divergence. ORT tumors displayed robust stromal activation, coordinated fibroblast and endothelial signaling, and an immune compartment marked by higher T/NK cell activation and IgA-biased B cell plasma programs, reflecting a physiological mucosal environment. In contrast, SC tumors had higher overall T cell infiltration but showed markedly increased CD8+ T cell exhaustion and an enriched oxidative tumor program. Our findings provide critical guidance: SC models are optimal for high-throughput and exhaustion-focused assays, whereas ORT models are indispensable for studying organ-specific immune and stromal biology with translational fidelity.
Authors: Jinho Jang, Yoojeong Seo, Kyung-Pil Ko, Jie Zhang, Sohee Jun, Jae-Il Park
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4414870833