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Insights into intestinal neuroendocrine tumors in relation to normal human EEC differentiation [ChIPseq]

ABSTRACT: Mutationally silent small intestinal neuroendocrine tumors (SI-NETs) characterized by few recurrent alterations, such as those that inactivate the cyclin-dependent kinase (CDK) inhibitor CDKN1B in <10% of cases are not well defined at the molecular level. Since the native enteroendocrine cells (EECs), which these tumors resemble, are scarce; the lack of reference data from normal EECs limits identification of gene and cis-element dysregulation in SI-NETs. We established transcriptional landscapes (RNA-seq) in bulk cultures and at single-cell (sc) resolution during the trajectory of normal human EEC differentiation from ileal stem cells in vitro (PMID 38733993). We compared the findings in SI-NETs against the novel reference profiles of normal human EEC differentiation and maturation. SI-NETs correspond principally to mature EC cells, with discernible features of non-EC and progenitor cells; persistent expression of the latter genes likely contributes to malignant properties. Underlying this aberrant expression pattern we found diverse SI-NET enhancers. EECs normally differentiate through an intermediate HES6hi/ASCL1+ oscillatory state before NEUROD1+ pre-terminal cells emerge; ASCL1 expression then persists only in mature EC cells. In contrast, although SI-NETs express NEUROD1, they strictly lack ASCL1 and other genes normally co-expressed with ASCL1. Notably, ASCL1 and loci encoding transcription factors that define non-EC cell types (ISL1, ARX, PAX6, PDX1) are marked with H3K27me3, signifying epigenetic silencing. SI-NETs express CDKN1B but other CDK inhibitors, e.g., CDKN2A and CDKN1C, are epigenetically silenced, suggesting that tumor cells may especially depend on wild-type CDKN1B function. Chromatin and transcriptional features of SI-NETs, revealed for the first time with respect to normal EEC differentiation, will help identify tumorigenic pathways and candidate therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277192 | GEO | 2026/04/29

REPOSITORIES: GEO

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Project description:Objective: Enteroendocrine cells (EECs) survey the gut luminal environment and co-ordinate hormonal, immune and neuronal responses to it. They exhibit well characterized physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in human gut. The small molecule Isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation. Methods: We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real time quantitative PCR, fluorescent activated cell sorting, immunostaining and single cell RNA sequencing. Results: ISX-9 increased the number of neurogenin3 (Ngn3) positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors which play roles in mouse EEC specification. Single cell analysis revealed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased towards serotonin-producing enterochromaffin (EC) cells. This coincided with enrichment of organoids with functional EC cells which was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types. Conclusion: Our data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications.

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Insights into intestinal neuroendocrine tumors in relation to normal human EEC differentiation [ChIPseq]

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