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LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[scMultiome-seq]

ABSTRACT: Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268957 | GEO | 2024/09/19

REPOSITORIES: GEO

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LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[CUT&RUN]

Project description:Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

2024-09-19 | GSE268956 | GEO

LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[scMultiome-seq]

Project description:LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[scMultiome-seq]

| PRJNA1119502 | ENA

High Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells

Project description:Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity and systemic metabolism and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences with murine EECs, including in hormones, sensory receptors and transcription factors. Notably, several novel hormone-like molecules were identified. Inter-EEC communication is exemplified by Secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.

2020-05-15 | PXD017468 | Pride

LSD1 promotes secretory cell specification to drive BRAFmutant colorectal cancer

Project description:Despite the connection to distinct mucus-containing colorectal cancer (CRC) histological subtypes, the role of secretory cells, including goblet and enteroendocrine (EEC) cells, in CRC progression has been underexplored. Analysis of TCGA and single cell RNA sequencing data demonstrates that multiple secretory progenitor populations are enriched in BRAF-mutant CRC patient tumors and cell lines. Enrichment of EEC progenitors in BRAF-mutant CRC is maintained by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of EECs. Mechanistically, secretory cells and the factors they secrete, such as Trefoil factor 3, are shown to promote colony formation and activation of cell survival pathways in the entire cell population. We further identify LSD1 as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss reduces tumor growth and metastasis. This work establishes EEC progenitors, in addition to goblet cells, as targetable populations in BRAF-mutant CRC and identifies LSD1 as a therapeutic target in secretory lineage-containing CRC.

2021-06-21 | GSE167262 | GEO

Comparison of enteroendocrine cells and pancreatic β-cells using gene expression profiling and insulin gene methylation

Project description:In this study, similarities between EECs and β-cells were evaluated in detail. To obtain specific subtypes of EECs, cell sorting by flow cytometry was conducted from STC-1 cells (a heterogenous EEC line), and each single cell was cultured and passaged. Five EEC subtypes were established according to hormone expression, measured by quantitative RT-PCR and immunostaining: L, K, I, G and S cells expressing glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, cholecystokinin, gastrin and secretin, respectively. Global microarray gene expression profiles revealed a higher similarity between each EEC subtype and MIN6 cells (a β-cell line) than between C2C12 cells (a myoblast cell line) and MIN6 cells, and all EEC subtypes were highly similar to each other. Genes for insulin secretion-related proteins were mostly enriched in EECs.

2018-09-11 | GSE119747 | GEO

Mucinous colorectal adenocarcinoma

Project description:Mucinous colorectal adenocarcinoma

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LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[CUT&RUN]

Project description:LSD1 and CoREST2 Regulate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer[CUT&RUN]

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An integral atlas of hormone peptides of human EECs and their dedicated proteases

Project description:Enteroendocrine cells (EECs) secrete hormones in response to ingested nutrients to control physiological processes such as appetite and insulin release. EEC hormones are synthesized as large pre-proteins that undergo proteolytic processing through peptidases to generate bioactive peptides. Due to the rarity of EECs and lack of cell models, prohormone processing remains challenging to assess. Here, we generated a panel of human organoid models in which EECs can efficiently be induced, combined with CRISPR-Cas9-mediated genetic inactivation or alteration of peptidases. We employed mass spectrometry based analysis to monitor peptide processing in knock-outs and wild type organoids for various hormone-processing enzymes (including PCSK1, PCSK2, PCSK1N, PCSK1mut_S375G, PCSK2mut_R430W, DPP4, CPB1 and CPE). We identify PCSK2-dependent Glucagon production in EECs, which is stimulated by activation of BMP signaling. We further map the substrates of other major EECs endo- and exopeptidases.

2022-11-26 | PXD033369 | Pride

An approach to intersectionally target mature enteroendocrine cells in the small intestine of mice

Project description:Enteroendocrine cells (EECs) constitute only a small proportion of Villin-1 (Vil1)-expressing intestinal epithelial cells (IECs) of the gastrointestinal tract; yet, in sum, they build the largest endocrine organ of the body, with each of them storing and releasing a distinct set of peptides for the control of feeding behavior, glucose metabolism, and gastrointestinal motility. Like all IEC types, EECs are continuously renewed from intestinal stem cells in the crypt base and terminally differentiate into mature subtypes while moving up the crypt-villus axis. Interestingly, EECs adjust their hormonal secretion according to their migration statues as EECs receive altering differentiation signals along the crypt-villus axis and thus undergo functional readaptation. Cell-specific targeting of mature EEC subtypes by specific promoters is challenging because the expression of EEC-derived peptides and their precursors are not limited to EECs but are also found in other organs, such as the brain (e.g. Cck and Sst) as well as in the pancreas (e.g. Sst and Gcg). Here, we describe an intersectional genetic approach that enables cell type-specific targeting of functionally distinct EEC subtypes by combining a newly-generated Dre-recombinase expressing mouse line (Vil1-2A-DD-Dre) with multiple existing Cre-recombinase mice, and mouse strains with rox and loxP sites flanked stop cassettes for transgene expression. We found that transgene expression in triple-transgenic mice is highly specific in I, but not D and L cells in the apical villi of the small intestine. The targeting of EECs only in villi is likely caused by the intrinsic Vil1 expression, limiting our Vil1-2A-DD-Dre mouse line and the intersectional genetic approach described here for the investigation of mature EECs.

2024-01-15 | GSE250433 | GEO

Unbiased transcription factor CRISPR screen identifies ZNF800 as master repressor of enteroendocrine differentiation [screen]

Project description:Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI) and colon. EECs regulate various aspects of metabolic activity including insulin levels, satiety, gastrointestinal secretion and motility. The generation of different EEC lineages of the SI is incompletely understood. We now report a TFome-wide CRISPR knockout screen in adult human intestinal organoids to identify dominant transcription factors controlling EEC differentiation. ZNF800 is discovered as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional SCRISPR screens for genes that program cell differentiation.

2023-10-27 | GSE229584 | GEO

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