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Origins, diversity and clinical relevance of small intestinal neuroendocrine tumors [methylation]

ABSTRACT: Small intestine neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells (EECs), which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such. Here, through the largest meta-omics analysis ever conducted on siNETs, we unveiled four distinct molecular groups with strong clinical relevance and provide an invaluable resource to study their origin and clinical features. Genetic and DNA methylation profiles identified two groups linked to distinct enteroendocrine differentiation patterns, another with a strong immune phenotype, and the last with mesenchymal properties. This latter subtype displayed the worst prognosis and resistance to treatments. These data provide new insights into the origin and diversity of these rare diseases, in the hope of improving clinical research into their management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229203 | GEO | 2025/01/10

REPOSITORIES: GEO

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Project description:Background: Endocrine cells of the digestive system, including the pancreatic endocrine cells (PECs) clustered in the islets of Langerhans and the enteroendocrine cells (EECs) scattered in the intestinal epithelium, play an important role in metabolism. Although EECs and PECs are located in distinct organs, they share many features and several common genes control their differentiation. In this study, we investigated comprehensively the similarity of EECs and PECs by defining their transcriptomic landscape and comparing the regulatory networks controlled by pax6b, a key player in both EECs and PECs. Results: RNA-sequencing was performed on EECs and PECs isolated from wild-type and pax6b mutant zebrafish. Data mining of wild-type zebrafish EEC data confirmed the expression of orthologs for most known mammalian EEC hormones but also revealed the expression of three additional neuropeptide hormones (Proenkephalin-a, Calcitonin-a and Adcyap1a) not yet reported to be expressed by EECs in any species. Comparison of transcriptomes from EECs, PECs and other zebrafish tissues highlights a very close similarity between EECs and PECs, with more than 70 % of genes being expressed in both endocrine cell types. Comparison of Pax6b-regulated genes in EECs and PECs revealed a significant overlap. pax6b loss-of-function does not affect the total number of EECs and PECs but instead disrupts the balance between cell subtypes, leading to an increase of ghrelin- and motilin-like expressing cells in both the intestine and pancreas at the expense of other endocrine cells such as beta- and delta-cells in the pancreas and pyyb-expressing cells in the intestine. Finally, we show that the homeodomain of Pax6b is dispensable for its action in both EECs and PECs. Conclusion: This study highlights the close relatedness of EECs and PECs at the transcriptomic and regulatory levels, supporting the hypothesis of a common phylogenetic origin and underscoring the potential implication of EECs in metabolic diseases such as Type 2 diabetes.

Project description:Background and aims: Enteroendocrine cells (EECs) and their hormones are essential regulators of whole-body energy homeostasis. EECs sense luminal nutrients and microbial metabolites and subsequently secrete a variety of hormones acting locally or at distance. Impaired development of EECs during embryogenesis is life-threatening in newborn mice and humans due to compromised nutrient absorption. However, the physiological importance of the EEC system in adult mice has not been directedly studied. Herein, we aimed to determine the long-term consequences of a total loss of EECs in healthy adults on energy metabolism, intestinal transcriptome and microbiota. Methods: We depleted intestinal EECs by tamoxifen treatment of adult Neurog3fl/fl; Villin-CreERT2 male mice. We studied intestinal cell differentiation, food efficiency, lipid absorption, microbiota composition, fecal metabolites and transcriptomic responses in the proximal and distal small intestine of mice lacking EECs. We also determined the high-fat diet induced transcriptomic changes in sorted Neurog3eYFP/+EECs. Results: Induction of EECs deficiency in adults is not life-threatening unless fed with a high-fat diet. Under a standard chow diet, mice lose 10% of weight due to impaired food efficiency. Blood concentrations of cholesterol, triglycerides, and free fatty acids are reduced and lipid absorption is impaired and delayed to the distal small intestine. Genes controlling lipogenesis, carbohydrate metabolism and neoglucogenesis are upregulated. Microbiota composition is rapidly altered after ECCs depletion and characterized by decreased -diversity. Bacteroides and Lactobacillus were progressively enriched while Lachnospiraceae declined without impacting fecal short chain fatty acid concentrations. Conclusions: EECs are dispensable for survival in adult male mice under a standard chow diet. The absence of EECs impairs intestinal lipid absorption leading to transcriptomic and metabolic adaptations and remodeling of the gut microbiota.

Project description:Background and aims: Enteroendocrine cells (EECs) and their hormones are essential regulators of whole-body energy homeostasis. EECs sense luminal nutrients and microbial metabolites and subsequently secrete a variety of hormones acting locally or at distance. Impaired development of EECs during embryogenesis is life-threatening in newborn mice and humans due to compromised nutrient absorption. However, the physiological importance of the EEC system in adult mice has not been directedly studied. Herein, we aimed to determine the long-term consequences of a total loss of EECs in healthy adults on energy metabolism, intestinal transcriptome and microbiota. Methods: We depleted intestinal EECs by tamoxifen treatment of adult Neurog3fl/fl; Villin-CreERT2 male mice. We studied intestinal cell differentiation, food efficiency, lipid absorption, microbiota composition, fecal metabolites and transcriptomic responses in the proximal and distal small intestine of mice lacking EECs. We also determined the high-fat diet induced transcriptomic changes in sorted Neurog3eYFP/+EECs. Results: Induction of EECs deficiency in adults is not life-threatening unless fed with a high-fat diet. Under a standard chow diet, mice lose 10% of weight due to impaired food efficiency. Blood concentrations of cholesterol, triglycerides, and free fatty acids are reduced and lipid absorption is impaired and delayed to the distal small intestine. Genes controlling lipogenesis, carbohydrate metabolism and neoglucogenesis are upregulated. Microbiota composition is rapidly altered after ECCs depletion and characterized by decreased alpha-diversity. Bacteroides and Lactobacillus were progressively enriched while Lachnospiraceae declined without impacting fecal short chain fatty acid concentrations. Conclusions: EECs are dispensable for survival in adult male mice under a standard chow diet. The absence of EECs impairs intestinal lipid absorption leading to transcriptomic and metabolic adaptations and remodeling of the gut microbiota.

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Origins, diversity and clinical relevance of small intestinal neuroendocrine tumors [methylation]

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