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Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation [scRNA-seq]

ABSTRACT: Cell state plasticity is carefully regulated in adult epithelia, enabling adaptive responses to stressors. The nongenetic factors that control aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation in neoplasia require deeper characterization. Using genetically-engineered and carcinogen-induced murine models of intestinal neoplasia, we demonstrate that impaired differentiation is a conserved event preceding cancer development. Single cell RNA-sequencing (scRNA-seq) of intestinal neoplasia from both mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed emergence of regenerative and fetal programs, and restored multi-lineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE224679 | GEO | 2023/04/03

REPOSITORIES: GEO

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Aberrant cell state plasticity mediated by developmental reprogramming precedes cancer initiation [CUT&RUN]

Project description:Cell state (phenotypic) plasticity is a carefully regulated feature of adult epithelial cells that enables adaptive responses to injury, inflammation, and other forms of stress.Aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation is a critical aspect of neoplasia. The nongenetic factors and specific programs that mediate aberrant cell state plasticity and impaired differentiationrequire deeper characterization to understand this elusive aspect ofcancer pathogenesis. Using genetically engineered andcarcinogen-induced murine models of intestinal neoplasia, wedemonstrate that impaired differentiation is a conserved eventpreceding cancer development. Single cell RNA-sequencing (scRNA-seq)of neoplastic intestinal lesions from both mouse models and a patientwith familial adenomatous polyposis revealed that cancer initiates byadopting an aberrant transcriptional state characterized bynonoverlapping expression of a regenerative pathway, marked by Ly6a(Sca-1), and a fetal intestinal program, positive for Tacstd2 (Trop2).Genetic inactivation of Sox9 prevented adenoma formation in ApcKOmice, obstructed emergence of aberrant regenerative and fetalintestinal programs, and restored multi-lineage differentiation byscRNA-seq. Expanded chromatin accessibility at regeneration and fetalgenes upon Apc inactivation was reduced by concomitant Sox9suppression. These studies indicate that aberrant cell stateplasticity mediated by unabated regenerative activity anddevelopmental reprogramming precedes cancer development.

2023-04-03 | GSE221299 | GEO

Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation [ATAC-seq]

2023-04-03 | GSE221298 | GEO

Transcription profiling by array of human colorectal cancer SW620 cells upon MSX1 depletion.

Project description:The first step in the development of human colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene encoding an essential tumor suppressor. In order to identify genes affected by Apc loss, expression profiling of intestinal epithelium isolated from mice harboring the conditional allele of the gene was performed. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Subsequently, the expression pattern of human MSX1 was examined in a collection of colonic tumors. The MSX1 mRNA level was increased in all types of human intestinal neoplasia tested. In order to identify genes affected by MSX1 loss, expression profiling of human colorectal cancer cells SW620 upon MSX1 gene depletion was performed.

2019-11-01 | E-MTAB-6928 | biostudies-arrayexpress

PTEN-deficient intestinal stem cells initiate intestinal polyposis

Project description:Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts. Crypts contain intestinal stem cells (ISCs). Thus intestinal polyposis provides an ideal condition for studying stem cell involvement in polyp/tumor formation. Using a conditional knock-out mouse model, we found that the tumor suppressor Phosphatase of Tension homolog (PTEN) governs the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN mutants, excess ISCs initiate de-novo crypt formation and crypt fission, recapitulating crypt production in fetal/neonatal intestine. Microarray studies were used to profile the changes in gene expression that occurred when PTEN was knocked out in the intestine. Keywords: Disease state analysis, genetic modification, Intestinal polyposis, PTEN mutant, Cowden disease mouse model

2006-11-18 | GSE6078 | GEO

Proteomics analysis of cerebrospinal fluid (CSF) from multiple sclerosis patients

Project description:Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represents an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis promote neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. We present the results of STEMS, a single dose escalation phase I clinical trial, evaluating the feasibility, safety, and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 PMS patients.

2022-11-18 | PXD034840 | Pride

Proteomics analysis of cerebrospinal fluid (CSF) from multiple sclerosis patients

2022-11-18 | PXD034846 | Pride

An organoid-based CRISPR/Cas9 screen for regulators of intestinal epithelial maturation

Project description:Generation of functionally mature organs requires exquisite control of transcriptional programs governing cell state transitions during development. Despite advances in understanding the behavior of adult intestinal stem cells and their progeny, the transcriptional regulators that control the emergence of the mature intestinal phenotype remain largely unknown. Using mouse fetal and adult small intestinal organoids, we uncover transcriptional differences between the fetal and adult state and identify rare adult-like cells present in fetal organoids. This suggests that fetal organoids possess an inherent potential to mature, which is locked by a regulatory program. By implementing a CRISPR/Cas9 screen targeting transcriptional regulators expressed in fetal organoids, we establish Smarca4 and Smarcc1 as important factors safeguarding the immature progenitor state. Our approach demonstrates the utility of organoid models in the identification of factors regulating cell fate and state transitions during tissue maturation and reveal that Smarca4 and Smarcc1 prevent precocious differentiation during intestinal development.

2023-07-13 | GSE221278 | GEO

Effect of colonic epithelial knockout of tumor necrosis factor receptor 2 (TNFR2) in dextran sulfate sodium (DSS)-induced colitis

Project description:Colonic epithelial repair is a key determinant of health. After injury, repair initiates through phenotypic reprogramming of wounded epithelium to a regenerative state permissive for the activation of alternative stem cell populations and healing. Although cytokine signals such as interferons may help induce regenerative reprogramming, the signals that modify this state as the wound resolves remain largely unknown. Here we examined whether cytokine signaling mediated by tumor necrosis factor receptor 2 (TNFR2) influenced the wound repair process. We examined mice with targeted deletion of the Tnfrsf1b (TNFR2) gene in intestinal/colonic epithelium (Vil1::Cre;Tnfr2-f/f) and compared their transcriptional profiles to control (Tnfr2-f/f) mice. We sorted EpCAM+ (epithelial) cells from Vil1::Cre;Tnfr2-f/f and control DSS-treated mice and performed bulk RNA-Seq. Comparison of transcript expression profile before and after DSS-induced colitis in control (Tnfr2-f/f) mice revealed upregulation of pathways associated with metabolic regulation, ribosomal function, oxidative stress, TNF signaling, and focal adhesions after DSS treatment. Pathway enrichment analysis demonstrated elevated regenerative (“fetal”) intestinal signaling, reduced inflammation, and increased proliferative signaling in Vil1::Cre;Tnfr2-f/f colonic epithelium after DSS treatment. The knockout epithelium also showed reduced expression of markers of differentiated colonic epithelium and elevated expression of progenitor cell signaling. Thus, the transcriptional data were consistent with increased regenerative signaling in TNFR2-knockout epithelium, suggesting that TNFR2 has a role in restraining the relatively undifferentiated regenerative state.

2023-08-22 | GSE230329 | GEO

Genes regulated by Sox9

Project description:We compared gene expression profile of jejunum crypt samples of Sox9 deficient mice and wild type control mice in order to identify the genes that are regulated by SOX9 in the small intestinal crypt epithelial cells. The intestinal epithelial cells were collected from crypts of jejunum of three 3-mo-old Sox9 mutant mice and three littermate controls.

2012-03-23 | E-GEOD-35481 | biostudies-arrayexpress

IκBα deficiency imposes a fetal phenotype to intestinal stem cells [RNA-seq]

Project description:The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBa, not only controls NF-κB activation, but also exerts nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. We now uncover nuclear phosphorylated IκBa (P-IκBa) in the ISC compartment where it binds highly histone methylated genomic regions. Mice deficient for IκBa show aberrant distribution of H3K27me3 mark, and altered intestinal differentiation with persistence of a fetal-like ISC signature. In vitro, IκBa deficient intestinal cells produced morphologically aberrant organoids carrying a PRC2, Notch and IFN-dependent fetal-like transcriptional signature. Induction of the fetal-like phenotype by DSS treatment is associated with loss of nuclear P-IκBa in the damaged colonic epithelium and it subsequent accumulation in early CD44 positive regenerating areas. Importantly, IκBa deficient animals showed higher resistance to damage, likely due to persistent fetal-like phenotype. These results point out intestinal IκBa as chromatin sensor of inflammation in the ISC compartment.

2020-02-04 | GSE131186 | GEO

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