Similar Datasets
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
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 | GSE232136 | GEO
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
Project description:In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion
| PRJNA971114 | ENA
Project description:In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [RNA-seq]
| PRJNA971121 | ENA
Project description:In vitro organoid-based assays reveal SMAD4 tumor-suppressive mechanisms for serrated colorectal cancer invasion [ChIP-seq]
| PRJNA971119 | ENA
Project description:BRAF-driven colorectal cancer is among the poorest prognosis subtypes of colon cancer. Previous studies suggest that BRAF-mutant serrated cancers frequently exhibit Microsatellite Instability (MSI) and elevated levels of WNT signaling. The loss of tumor-suppressor Smad4 in oncogenic BRAF-V600E mouse models promotes rapid serrated tumor development and progression, and SMAD4 mutations co-occur in human patient tumors with BRAF-V600E mutations. This study assesses the role of SMAD4 in early-stage serrated tumorigenesis. SMAD4 loss promotes microsatellite stable (MSS) serrated tumors in an oncogenic BRAF-V600E context, providing a model for MSS serrated cancers. Inactivation of Msh2 in these mice accelerated tumor formation, and whole-exome sequencing of both MSS and MSI serrated tumors derived from these mouse models revealed that all serrated tumors developed oncogenic WNT mutations, predominantly in the WNT-effector gene Ctnnb1 (β-catenin). Mouse models mimicking the oncogenic β-catenin mutation show that the combination of three oncogenic mutations (Ctnnb1, Braf, and Smad4) are critical to drive rapid serrated dysplasia formation. Re-analysis of human tumor data reveals BRAF-V600E mutations co-occur with oncogenic mutations in both WNT and SMAD4/TGFβ pathways. These findings identify SMAD4 as a critical factor in early-stage serrated cancers and helps broaden the knowledge of this rare but aggressive subset of colorectal cancer.
| S-EPMC8559887 | biostudies-literature
Project description:BackgroundTumor metastasis is one of the leading causes of poor prognosis for colorectal cancer (CRC) patients. Loss of Smad4 contributes to aggression process in many human cancers. However, the underlying precise mechanism of aberrant Smad4 expression in CRC development is still little known.ResultsmiR-20a-5p negatively regulated Smad4 by directly targeting its 3'UTR in human colorectal cancer cells. miR-20a-5p not only promoted CRC cells aggression capacity in vitro and liver metastasis in vivo, but also promoted the epithelial-to-mesenchymal transition process by downregulating Smad4 expression. In addition, tissue microarray analysis obtained from 544 CRC patients' clinical characters showed that miR-20a-5p was upregulated in human CRC tissues, especially in the tissues with metastasis. High level of miR-20a-5p predicted poor prognosis in CRC patients.MethodsFive miRNA target prediction programs were applied to identify potential miRNA(s) that target(s) Smad4 in CRC. Luciferase reporter assay and transfection technique were used to validate the correlation between miR-20a-5p and Smad4 in CRC. Wound healing, transwell and tumorigenesis assays were used to explore the function of miR-20a-5p and Smad4 in CRC progression in vitro and in vivo. The association between miR-20a-5p expression and the prognosis of CRC patients was evaluated by Kaplan-Meier analysis and multivariate cox proportional hazard analyses based on tissue microarray data.ConclusionsmiR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in CRC cells, and high miR-20a-5p predicted poor prognosis for CRC patients, providing a novel and promising therapeutic target in human colorectal cancer.
| S-EPMC5216716 | biostudies-literature
Project description:Profiling heterologous cell types within tumors is essential to decipher tumor microenvironment that shapes tumor progress and determines the outcome of therapeutic response. Here, we comprehensively characterized transcriptomes of 34,037 single cells obtained from 12 treatment-naïve patients with colorectal cancer. Our comprehensive evaluation revealed attenuated B-cell antigen presentation, distinct regulatory T-cell clusters with different origin and novel polyfunctional tumor associated macrophages associated with CRC. Moreover, we identified expanded XCL1+ T-cell clusters associated with tumor mutational burden high status. We further explored the underlying molecular mechanisms by profiling epigenetic landscape and inferring transcription factor motifs using single-cell ATAC-seq. Our dataset and analysis approaches herein provide a rich resource for further study of the impact of immune cells and translational research for human colorectal cancer.
| S-EPMC8181206 | biostudies-literature
Project description:Introduction: Termite symbionts are well known for conferring a myriad of benefits to their hosts. Bacterial symbionts are repeatedly associated with increased fitness, nutritional supplementation, pathogen protection, and proper development across insect taxa. In addition, several recent studies link bacterial symbionts to reduced insecticide efficacy. This has important implications both in pest control management and environmental bioremediation efforts. Insects' guts may be a valuable resource for microbes with broad application given their unique niches and metabolic diversity. Though insecticide resistance in termites is considered unlikely due to their life history, the close association of termites with a multitude of bacteria raises the question: is there potential for symbiont-mediated pesticide tolerance in termites? Methods and results: We identified a candidate that could grow in minimal medium containing formulated pesticide. This bacterial isolate was then subjected to continuous culture and subsequently demonstrated improved performance in the presence of pesticide. Isolates subjected to continuous culture were then grown at a range of concentrations from 1-10X the formulation rate. After constant exposure for several generations, isolates grew significantly better. Conclusion: Here we demonstrate that naïve insect hosts can harbor symbionts with inherent insecticide tolerance capable of rapid adaptation to increasing insecticide concentrations overtime. This has broad implications for both pest control and environmental cleanup of residual pesticides.
| S-EPMC10368989 | biostudies-literature