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In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [ChIP-seq]

ABSTRACT: In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [ChIP-seq]

PROVIDER: PRJNA971119 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24491490.fastq.gz	Fastqsanger.gz
	SRR24491491.fastq.gz	Fastqsanger.gz

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In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion

Project description:In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion

| PRJNA971114 | ENA

In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [RNA-seq]

Project description:In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [RNA-seq]

| PRJNA971121 | ENA

In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [RNA-seq]

Project description:We establish a model system where organoids derived from tumors found in the Smad4KO BRAFV600E/+ mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems. Additionally, Smad4KO BRAFV600E/+ tumor organoids have the ability to infiltrate a transwell and initiate colonies on the culture plate below. This invasive behavior can be suppressed when SMAD4 is re-expressed in the tumor organoids. RNA-Seq analysis reveals that SMAD4 expression in organoids rapidly regulates transcripts associated with extracellular matrix and secreted proteins, suggesting that the mechanisms employed by SMAD4 to inhibit invasion are associated with regulation of extracellular matrix and secretory pathways. These findings indicate new models to study SMAD4 regulation of tumor invasion and an additional layer of complexity in the tumor-suppressive function of the SMAD4/Tgfβ pathway.

2024-05-30 | GSE232137 | GEO

In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [ChIP-seq]

2024-05-30 | GSE232136 | GEO

In Vitro Organoid-Based Assays Reveal SMAD4 Tumor-Suppressive Mechanisms for Serrated Colorectal Cancer Invasion.

Project description:Colon cancer is the third most prominent cancer and second leading cause of cancer-related deaths in the United States. Up to 20% of colon cancers follow the serrated tumor pathway driven by mutations in the MAPK pathway. Loss of SMAD4 function occurs in the majority of late-stage colon cancers and is associated with aggressive cancer progression. Therefore, it is important to develop technology to accurately model and better understand the genetic mechanisms behind cancer invasion. Organoids derived from tumors found in the Smad4KO BRAFV600E/+ mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems. Smad4KO BRAFV600E/+ tumor organoids can migrate through 3D culture and infiltrate through transwell membranes. This invasive behavior can be suppressed when SMAD4 is re-expressed in the tumor organoids. RNA-Seq analysis reveals that SMAD4 expression in organoids rapidly regulates transcripts associated with extracellular matrix and secreted proteins, suggesting that the mechanisms employed by SMAD4 to inhibit invasion are associated with regulation of extracellular matrix and secretory pathways. These findings indicate new models to study SMAD4 regulation of tumor invasion and an additional layer of complexity in the tumor-suppressive function of the SMAD4/Tgfβ pathway.

| S-EPMC10742020 | biostudies-literature

In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-30 | GSE232138 | GEO

Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling

Project description:Loss of TGF-beta growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-beta resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich protein (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers, such as Hepatocellular carcinoma (HCC). In this study, we identified SFPQ as a potent suppressor of TGF-beta signaling. The ability of SFPQ to suppress TGF-beta responses depended on its prion-like domain (PrLD) that drives phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy, and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of LLPS rendered cells hypersensitive to TGF-beta responses. Together, our data reveal a unique function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-beta tumor-suppressive activity.

2023-11-16 | GSE236125 | GEO

Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling

Project description:Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling

| PRJNA989100 | ENA

Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis.

Project description:Objective: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases, and includes tumours that are amongst the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen activated kinase (MAPK) pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype (CIMP), leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. Design: We utilise organoid culture combined with CRISPR/Cas9 genome engineering, to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. Results: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. Conclusion: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.

2018-04-30 | GSE112774 | GEO

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis (AKPS_EV_vs_Smad4_RNAseq)

Project description:RNA-sequencing of TGFβ treated empty vector (EV) or Smad4-expressing AKPS lines followed by GSEA revealed a number of gene sets overlapping with those obtained from analyses in reactive cholangiocytes. Hallmark gene sets MYC, E2F, G2M checkpoint, and oxidative phosphorylation were enriched with loss of Smad4, while TGFβ signaling, EMT, and TNFα were enriched with intact Smad4 signaling, suggesting conserved growth suppressive functions of Smad4 in primary cholangiocytes and advanced cancer.

2023-12-07 | GSE237679 | GEO

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