Ontology highlight
ABSTRACT:
PROVIDER: PRJNA600246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10858658.fastq.gz | Fastqsanger.gz | |||
| SRR10858659.fastq.gz | Fastqsanger.gz | |||
| SRR10858660.fastq.gz | Fastqsanger.gz | |||
| SRR10858661.fastq.gz | Fastqsanger.gz | |||
| SRR10858662.fastq.gz | Fastqsanger.gz |
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Project description:Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We found that microbial metabolites from healthy mice or humans were growth-repressive, and this response was attenuated in mice and patients with CRC. Microbial profiling revealed that Lactobacillus reuteri and its metabolite, reuterin were downregulated in mouse and human CRC. Reuterin altered redox balance, and reduced survival, and proliferation in colon cancer cells. Reuterin induced selective protein oxidation, and inhibited ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricted mouse colon tumor growth, increased tumor reactive oxygen species, and decreased protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
2021-12-12 | GSE186880 | GEO
Project description:Inflammatory injury to the intestine triggers a reprogramming of the intestinal epithelium to a fetal-like state, facilitating rapid restoration of the epithelial barrier. Although the intestinal microbiota is a key modulator of inflammation, its role in driving epithelial fetal-like reversion and promoting restitution remains unclear. Using irradiation (IR) injury as a model for small intestinal epithelium restitution, we found that the intestinal microbiota accelerated epithelial restitution by amplifying a repair-associated inflammatory response that promoted the emergence of fetal-like intestinal epithelial cells (IECs), marked by Ly6a and Clu. NOD2, the strongest genetic link to the development of Crohn’s disease, was expressed in fetal-like IECs following injury. Notably, stimulation of NOD2 by its peptidoglycan ligand in an ileal organoid model potentiated an inflammatory gene signature characterized by interferon (IFN) signaling, coinciding with enterocyte recovery. NOD2 deficiency exacerbated epithelial apoptosis following IR injury, while epithelial-specific NOD2 signaling promoted the emergence of fetal-like IECs and enhanced epithelial proliferation. Together, these results identify a critical role for microbiota and microbial sensing by NOD2 in controlling the fate of fetal-like IECs following injury, thereby contributing to the protective effect of this microbial sensor during intestinal inflammation.
2026-04-29 | GSE295472 | GEO
Project description:Loss of the tumor suppressor APC, which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces expression of RNA polymerase I (RNAPOL1) transcription machinery and subsequently upregulates rDNA transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity and induces a disbalance of ribosomal proteins. CX5461-induced growth arrest is irreversible, and exhibits features of senescence as well as terminal differentiation. Mechanistically, CX5461 promotes differentiation in a MIZ1- and Rb-dependent manner. In addition, inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents.
2022-05-31 | GSE204749 | GEO
Project description:Background and aims: Gut microbial metabolites and their host signaling pathways hold therapeutic potential for colorectal cancer (CRC). One example is short-chain fatty acids (SCFA), which are microbial metabolites generated from dietary fiber. This study aims to determine the pathogenesis of CRC from the host-microbiota perspective and the contributions of Ffar2, a SCFA receptor, to CRC. Methods: We have employed Apc-based models of CRC in conjunction with Ffar2 knock-out (ko) mice, Ffar2 conditional ko mice, and Ffar2 chemical agonism to reveal how a microbial metabolite receptor influences tumorigenesis in the colon. Utilizing human CRC datasets from The Cancer Genome Atlas aided our discovery of the links between Ffar2 function in dendritic cells and tumoral T cell dysfunction. Herein, we also used preclinical CRC models to test IL-27p28 neutralization or Ffar2 agonism as proof of concept for CRC prevention and treatment. Results: We have identified a mechanism by which Ffar2 deficiency potentiates tumorigenesis by affecting gut barrier integrity that increases tumor bacterial load and then altering IL-27+ dendritic cell populations and tumor CD8+ T cell phenotype and function. These events create a tumor immune milieu notable for dying and over-activated DCs and exhausted CD8+ T cells, which enables tumor growth. Proof-of-concept experiments in mice employing IL-27p28 neutralization or Ffar2 agonism reduced tumor burden. Conclusions: Our data support that loss of Ffar2 signaling potentiates tumorigenesis via a “two-hit” model, first by gut barrier breach and then by immune cell dysfunction. Our work supports that altering Ffar2 signaling or neutralizing IL-27 represent potential immunotherapy CRC treatment strategies.
2020-01-16 | GSE142691 | GEO
Project description:KRAS signaling is a promising target for cancer treatment, and the development of molecular targeted therapies has significantly improved the treatment outcome. However, cancer cells often adopt drug tolerant state to impede efficacy of chemotherapeutic agents. In colorectal cancer (CRC), therapeutic agents targeting KRAS have often failed to demonstrate a significant benefit, and the elucidation of its mechanism has been major clinical challenge. Here we show that MEK inhibitor, trametinib, and allele specific KRAS inhibitor, AMG510, induce the cellular state resembling the pluripotent naïve grand state of embryonic stem cells (ESCs). These cells are characterized by elevated ribosome biogenesis with Myc expression profile, yet global protein synthesis rate is low. We found they were vulnerable to the inhibition of ribosome biogenesis, and RNA polymerase I (RNA PolI) inhibition showed synergistic anti-tumor effects with trametinib and AMG510 in the autochthonous mouse model of intestinal tumors and in human patient-derived organoids with KRAS G12C mutation, respectively. These observations in PDOs demonstrated that CRC cells are equipotent to enter the pluripotent stem-like state by exploiting the cellular program of early embryogenesis and become tolerant to KRAS inhibition. High ribosome biogenesis is indispensable to maintain this cell state and is a potential therapeutic target of these cells. Our findings uncover previously unrecognized mechanisms of drug tolerance of CRC to KRAS inhibition, and provide the clue for the development of therapeutic strategies.
2025-08-10 | GSE264485 | GEO
Project description:Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of CRC and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune responses. As such, the complement system is an important determinant in the maintenance of intestinal homeostasis and emerging evidences suggest that complement dysregulation is involved in the development and progression of CRC. Here we show that in CRC patients CpG island methylation occurs in the gene encoding for the complement anaphylatoxin C3a receptor (c3aR) and strong C3aR down-regulation resulted in decreased overall survival and events-free survival in CRC patients. Ablation of c3ar in mouse models of CRC resulted in the establishment of a pro-inflammatory microbial flora, which fostered strong Th1/Th17 immune responses and a striking increase in tumor incidence and growth that were both dependent on the microbiota. Our findings highlight a previously unrecognized tumor oncosuppressive role for C3aR in CRC that could be exploited as a biomarker for more effective therapeutic intervention.
2020-02-01 | E-MTAB-8500 | biostudies-arrayexpress
Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer
This model is described in the article:
Model-based prediction of
phase III overall survival in colorectal cancer on the basis of
phase II tumor dynamics.
Claret L, Girard P, Hoff PM, Van
Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R.
J. Clin. Oncol. 2009 Sep; 27(25):
4103-4108
Abstract:
PURPOSE: We developed a drug-disease simulation model to
predict antitumor response and overall survival in phase III
studies from longitudinal tumor size data in phase II trials.
METHODS: We developed a longitudinal exposure-response
tumor-growth inhibition (TGI) model of drug effect (and
resistance) using phase II data of capecitabine (n = 34) and
historical phase III data of fluorouracil (FU; n = 252) in
colorectal cancer (CRC); and we developed a parametric survival
model that related change in tumor size and patient
characteristics to survival time using historical phase III
data (n = 245). The models were validated in simulation of
antitumor response and survival in an independent phase III
study (n = 1,000 replicates) of capecitabine versus FU in CRC.
RESULTS: The TGI model provided a good fit of longitudinal
tumor size data. A lognormal distribution best described the
survival time, and baseline tumor size and change in tumor size
from baseline at week 7 were predictors (P < .00001).
Predicted change of tumor size and survival time distributions
in the phase III study for both capecitabine and FU were
consistent with observed values, for example, 431 days (90%
prediction interval, 362 to 514 days) versus 401 days observed
for survival in the capecitabine arm. A modest survival
improvement of 39 days (90% prediction interval, -21 to 110
days) versus 35 days observed was predicted for capecitabine.
CONCLUSION: The modeling framework successfully predicted
survival in a phase III trial on the basis of capecitabine
phase II data in CRC. It is a useful tool to support
end-of-phase II decisions and design of phase III studies.
This model is hosted on
BioModels Database
and identified by:
MODEL1708310001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-08-31 | MODEL1708310001 | BioModels
Project description:The heat-shock protein 90 (HSP90) is a promising target in cancer therapy, but its inhibitors' clinical trial failures are partly due to a compensatory heat-shock response (HSR) mediated by heat-shock factor 1 (HSF1). We previously showed that wildtype p53 reduces HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we explore if simultaneous p53 activation or cell cycle inhibition can disrupt the HSF1-HSR axis and enhance HSP90 inhibitors' efficiency. mRNA sequencing was performed on HCT116 cells treated for 24 hours with DMSO, 50 nM Ganetespib, 1 µM RG-7388, or their combination. We found that the p53 activator Idasanutlin suppresses HSF1-HSR activity in HSP90 inhibitor-based therapies, synergistically reducing cell viability and accelerating cell death in p53-proficient colorectal cancer (CRC) cells and organoids. Combination therapy upregulates p53 pathways, apoptosis, and inflammation. In a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and alters immune cell composition. CDK4/6 inhibition under HSP90 inhibition mimics HSR repression in p53-proficient CRC cells. In p53-deficient CRC cells and p53-mutated organoids, combined HSP90 and CDK4/6 inhibition suppresses HSF1-HSR and reduces cancer growth, offering a p53-independent strategy for CRC treatment. In conclusion, we present new options to improve HSP90-based therapies for enhanced CRC treatment.
2025-03-28 | E-MTAB-14877 | biostudies-arrayexpress
Project description:Chemoresistance in cancer is linked to a subset of cancer cells termed “cancer stem cells” (CSCs), and in particular, those expressing the CD44 variant appear to represent a more aggressive disease phenotype. Herein, we demonstrate that CD44v6 represents a CSC population with increased resistance to chemotherapeutic agents, and its high expression is frequently associated with poor overall survival (OS) (HR:3.04; CI:1.35–6.85; p<0.001) and disease-free survival (DFS) (HR:5.30, CI:1.64–17.12, p<0.01) in CRC patients. CD44v6+ cells showed elevated resistance to chemotherapeutic drugs and significantly high tumor initiation capacity. The inhibition of CD44v6 resulted in the attenuation of self-renewal capacity and re-sensitization to chemotherapeutic agents. Of note, miRNA profiling of CD44v6+ SDCSCs identified a unique panel of miRNAs indicative of high self-renewal capacity. In particular, miR-1246 was overexpressed in CD44v6+ cells, and associated with poor OS (HR:2.44, CI:1.15–5.18, p<0.05) and DFS (HR:2.37, CI:1.03–5.44, p<0.05) in CRC patients. We demonstrate that CD44v6+ CSCs induced chemoresistance and enhance tumorigenicity in CRC cells, which is in part orchestrated by dysregulated profiles of a distinct panel of miRNAs. These findings provide a rationale for the therapeutic targeting of specific miRNAs, as well as serving as promising prognostic biomarkers in patients with colorectal neoplasia.
2019-02-22 | GSE125904 | GEO
Project description:Gut microbiome significantly influences immunotherapy responses in colorectal cancer (CRC) treatment. While individual enterobacteria have been identified as enhancers of anti-PD-1/anti-PD-L1 therapy, the synergistic effects of multiple enterobacteria remain underexplored. To fill the gap, we introduced Tumor-Suppressing Multi-Enterobacteria (TSME), a consortium of nine beneficial intestinal probiotic strains, and investigated its impact on the anti-PD-1/anti-PD-L1 therapy for microsatellite stable (MSS) CRC. Using a tumor-bearing mouse model and genomic sequencing techniques, our research demonstrated that TSME significantly improved therapy efficacy by optimizing tumor immune microenvironment. Specifically, the addition of TSME notably increased CD8+ T infiltration, modulated cytokine profiles, and up-regulated crucial immune-related pathways, including TNF and JAK-STAT. Additionally, TSME altered intestinal microbial composition, enriching beneficial bacteria such as Akkermansia and Alistipes. These findings suggest that the well-engineered multi-enterobacteria could significantly enhance the effectiveness of immunotherapy for MSS CRC by synergistically modulating the immune and microbial landscapes.
2026-04-26 | GSE271663 | GEO