Single-cell transcriptomic analysis of small intestinal neuroendocrine tumors revealed potential mechanisms of mesenteric fibrosis (A04)

Introduction: Nearly half of patients with small intestinal neuroendocrine tumor (SI-NET) experienced local mesenteric fibrosis (MF), significantly impacting their prognosis. However, the mechanism by which SI-NET causes MF remains unclear.

Aim(s): We aim to elucidate the molecular mechanisms underlying SI-NET fibrosis and explore potential therapeutic targets.

Materials and methods: We conducted single-cell RNA sequencing (scRNA) on 5 primary tumor specimens and their corresponding adjacent non-tumor tissues, integrating one public SI-NET scRNA data. Samples were grouped into SI-NET with MF (SINET_MF) and without MF (SINET_NF) groups based on pathological or radiological data. We obtained bulk RNA-seq data from public databases and performed validation using immunohistochemistry staining and ELISA.

Results: After dimensionality reduction and clustering, all samples were categorized into eight major cell lineages. IGFBP3 expression was notably higher in SINET_MF tumor cells compared to SINET_NF. The IGFBP3-related gene signature was related to fibroblasts, endothelial cells (EC) and perivascular-like cells (PVL). FIB_LUM, a matrix phenotype, was significantly enriched in SINET_MF. Trajectory and cell-cell interaction analysis revealed that IGFBP3 binds to the TGFβ2/3 receptors of FIB_LUM, activating TGFβ signaling pathway, thereby promoting MF. EC_ESM1, responsible for vascular budding, was enriched in tumors. IGFBP3 might promote the proliferation of EC_ESM1 by activating the PI3K-AKT signaling pathway. Immature PVL might cause endothelial destabilization and vascular leakage through ANGPT2-TIE2 interaction with EC in tumors.

Conclusion: We revealed a potential mechanism underlying fibrosis in SINET, suggesting IGFBP3 as a potential drug target and biomarker for SI NET fibrosis.

Keywords: small intestinal neuroendocrine tumor, single-cell rna sequencing, mesenteric fibrosis, fibroblasts