Characterising the tumor microenvironment of multifocal small intestinal NETs (A15)

Introduction: Small intestinal neuroendocrine tumors (SI-NETs) are thought to arise from enterochromaffin cells of the gut, often with multiple synchronous primary tumors. Recently, we showed that synchronous primary tumors from the same SI-NET patient display distinct somatic mutational profiles, suggesting that these tumors originate independently, despite few clear driver mutations. Thus, new mechanistic insights into multifocal SI-NETs are urgently needed.

Aim(s): To study the role of tumor microenvironment in the growth and development of multifocal SI-NETs.

Materials and methods: Our sample cohort included 75 synchronous primary tumors, 15 metastases, and their matched normal ileum from 13 patients with multifocal SI-NETs. We performed whole genome and single-nuclei RNA sequencing to study the tumor microbiome, stromal cell diversity, and gene expression in these lesions.

Results: Most microbial reads identified in our sample cohort were derived from bacteria, including known gut microbial phyla, such as Firmicutes, Bacteroidetes and Fusobacteria. Thus far, we do not find microbial species enriched in the tumors compared to matched normal ileum. At the single-cell level, we have identified enterochromaffin cells in normal ileum samples, allowing us to define their transcriptomic profile and use that as a reference for cancer-to-normal cell comparisons.

Conclusion: Finding the causes of multifocal SI-NETs is essential for decisions regarding prevention, treatment, surgery, and patient outcome. Understanding the dynamic interactions of cancer cells with their microenvironment will help to illuminate tumor biology.

Keywords: small intestinal net, tumor microenvironment, tumor microbiome