Cellule entéro-endocrine | EPFL Graph Search

Les cellules entéro-endocrines sont des cellules spécialisées du tractus gastro-intestinal et du pancréas à fonction endocrine. Elles produisent des peptides et des hormones gastro-intestinales en réponse à divers stimuli et les libèrent dans le sang pour obtenir un effet systémique (effet endocrine) ou les diffusent sous forme de messagers locaux (effet paracrine) ou les transmettent au système nerveux entérique pour y activer les réponses nerveuses. Les cellules entéro-endocrines de l'intestin sont les cellules endocrines les plus nombreuses du corps. Elles constituent un système endocrinien entérique en tant que sous-ensemble du système endocrinien, tout comme le système nerveux entérique est un sous-ensemble du système nerveux. Ces cellules agissent en tant que chimiorécepteurs, initiant des actions digestives, détectant des substances nocives et déclenchant des réponses protectrices. Les cellules entéro-endocrines sont situées dans l'estomac, l'intestin et le pancréas. Cellu

Intestinal stem cells differentiation and its application in cancer therapy

Maxim Norkin

Colorectal cancer (CRC) is one of the deadliest cancers worldwide. Despite extensive research in the field, new therapies targeting CRC are in urgent need. CRC is a highly heterogeneous disease with high levels of intra- and inter-patient heterogeneity. Cancer stem cells are the driving force of tumor development and metastasis. One of the approaches to treat CRC is differentiation therapy thereby induction of cancer stem cell differentiation may lead to tumor regression. Intestinal normal and cancer organoids represent an ideal model for studying the differentiation process ex vivo. Gene expression profiling of drug-treated organoids can be used for quantification of the differentiation process with high precision. RNA-seq based drug-screening platforms in organoids are not yet established. Here we developed a high-throughput high-content targeted RNA-seq-based platform (TORNADO-seq) for monitoring gene expression of large gene signatures in intestinal organoids which allowed us to quantify and evaluate complex cellular phenotypes and cellular alterations upon drug treatment. We applied TORNADO-seq in drug screening in wt and cancer intestinal organoids. We found many differentiation-inducing drugs in wt organoids, including some drugs specifically enriching for certain cell phenotypes, e.g. enteroendocrine cells. Further, we applied identified differentiation-inducing drugs to cancer organoids (APClof;KRASG12D;TP53lof) and discovered that the majority of those differentiation-inducing drugs also targeted cancer organoids. Differentiation induction seems to be a common mode of action of cancer-targeting drugs. Based on gene expression profiles of treated cancer organoids, we were able to propose and confirm the mechanism of action of several drugs indicating that cancer cells may to be sensitive to alterations in the cholesterol biosynthesis pathway. In general, utilization of TORNADO-seq allows predicting connections between cellular phenotypes and signaling pathways in organoids which can be used for hypothesis generation in a variety of biological systems. The second part of the thesis is devoted to the investigation of mechanisms underlying the accumulation of genetic alterations in CRC tumors. It is not known whether cancer driver genes affect the rate of mutation acquisition. Here we performed exome sequencing of single cell-derived organoids obtained from tumors with either APClof, APClof;KRASG12D or APClof;KRASG12D;TP53lof mutation phenotypes that reflect early stages of CRC development. We discovered that presence of KRAS and P53 mutations didn't affect the number of single nucleotide substitutions (SNSs) in tumors, while the latter was increased in APC mutated tumors compared to wt cells and was highly correlated with the tumor age. P53 inactivation was highly correlated with the presence of large-scale (>10 Mb) copy number alterations (CNAs).

EPFL2021

Anti-Obesity and Anti-Hyperglycemic Effects of Cinnamaldehyde via altered Ghrelin Secretion and Functional impact on Food Intake and Gastric Emptying

Susana Camacho Romero, Johannes Le Coutre, Henry Markram, Julie Meystre, Maurizio Ferdinando Pezzoli

Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention.

Nature Publishing Group2015

Intestinal stem cells differentiation and its application in cancer therapy

Maxim Norkin

EPFL2021