Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA360831 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We noticed that a recently identified poor prognosis stem/serrated molecular subtype of colorectal cancer (CRC) is characterized by up-regulation of transcripts known to be also expressed by stromal cells. To better define the origin of such transcripts, we analyzed RNAseq and microarray datasets from CRC mouse xenografts, where human cancer cells are supported by murine stroma. The analysis revealed that mRNA levels of stem/serrated subtype genes are mostly due to stromal expression, even when the stromal fraction is below 5%. Indeed, a classifier based on genes exclusively expressed by cancer-associated fibroblasts was significantly associated, in multiple datasets, to poor prognosis of CRC and to radioresistance of rectal cancer. Molecular Characterization of 72 primary rectal cancer formalin-fixed, paraffin-embedded (FFPE) specimens including 58 pretreatment specimens, 14 surgical specimens.
2014-05-01 | E-GEOD-56699 | biostudies-arrayexpress
Project description:Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To comprehensively identify such signaling pathways we profiled pretreatment biopsies from 65 patients with locally advanced rectal cancer – 30 of which carried mutated KRAS - using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted p-value p<0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations resulted in significant upregulation of 13 genes (adjusted p-value < 0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has been achieved therapeutically with the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively, suggesting a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas. Paired samples of tumor and mucosa from a total of 65 patients, i.e. 130 arrays
2011-03-11 | E-GEOD-20842 | biostudies-arrayexpress
Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1 (IL-1 dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.
2022-02-08 | PXD020871 | Pride
Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1a (IL-1a) dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.
2022-02-08 | PXD030422 | Pride
Project description:Tumor stroma strongly influences behaviour of cancer cells. Here, we study influence of the tumor stroma on transcription activity of head and neck squamous cell carcinoma cells. In particular, we compare transcription activity of the cancer cells in relation to expression of a putative prognostic marker tenascin in the surrogate of the tumor stroma, margin of surgical resecate.
2018-12-31 | E-MTAB-5852 | biostudies-arrayexpress
Project description:Total mesorectal excision (TME) is the standard treatment for rectal cancer, while transanal endoscopic microsurgery (TEM) is a recently introduced surgical approach for the treatment of rectal adenomas. Incorrect preoperative staging before TEM is a problem. To identify genetic changes that might correlate with tumour stage and could lead to optimized treatment selection we performed a genome-wide chromosomal instability search in a homogeneous, clinical cohort of rectal tumours. 78 rectal tumours during different clinical stages were analysed with 10K single nucleotide polymorphism (SNP) arrays. Logistic regression was performed to build a quantitative model of specific chromosomal aberrations. Overall, most cases (95%) had one or more chromosomal aberrations. We observed a clear correlation between the total number of aberrations and the different tumour stages. Specifically, the chromosomal events: gain of 8q22â24, 13q and 20q, and loss of 17p and 18q12â22, were far more abundant in carcinoma than in adenoma. In adenoma fractions from cases with a carcinoma (infiltrating at least in the submucosa), twice the amount of such âmalignant aberrationsâ was observed, compared to pure adenomas. Furthermore, combined aberrations such as gain of 13q and loss of 18q were only found in adenomatous fractions of carcinomas and not in benign lesions. Based on these five genomic events associated with carcinoma, a clear distinction between adenoma and carcinoma tissue could be made. These data should be validated further in order that they may be used in preoperative staging of rectal tumours. Experiment Overall Design: 78 tumor samples and 19 reference normal samples
2008-06-17 | E-GEOD-7946 | biostudies-arrayexpress
Project description:Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To comprehensively identify such signaling pathways we profiled pretreatment biopsies from 65 patients with locally advanced rectal cancer – 30 of which carried mutated KRAS - using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted p-value p<0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations resulted in significant upregulation of 13 genes (adjusted p-value < 0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has been achieved therapeutically with the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively, suggesting a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas.
2011-03-11 | GSE20842 | GEO
Project description:Although preoperative chemoradiotherapy (CRT) and surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas, it is still difficult to predict which patients will respond to treatment. We explored how differential stromal transcriptomic profiles from microdissected pretreatment rectal biopsies can be used to define an immunohistochemical score based on two CAF-specific proteins for predicting neoadjuvant treatment response. The analysis of differentially expressed genes (DEGs) of stroma and tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment. Gene ontology analysis revealed that the DEGs codify mainly for extracellular matrix and ribosomal components. We built a CAF-specific classifier with genes showing monotonic changes in expression according to the tumour regression grade (coefficient >1; FN1, COL3A1, COL1A1, MMP2 and IGFBP5). These are the genes that display the biggest a priori differences in expression between non-responder and responder stroma. We translated these five genes at the protein level by means of immunohistochemical staining in a cohort of 38 patients. For predictive purposes we used a leave-one-out cross-validated (LOOCV) model with a positive predictive value (PPV) of 80%. Classifier optimisation with Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the LOOCV regression model improved the classification performance with a PPV of 89.5% and a negative predictive value (NPV) of 73.7%. An independent cohort of 36 patients was used to validate the classifier performance, which had a PPV of 84.2% and an NPV of 70.6%. In a multivariate analysis the two-protein classifier proved to be the only independent predictor of response (HR=2.58; P=0.003). We also explored a pharmacogenomic approach to gather information about possible therapeutic strategies for non-responder patients. In conclusion, we developed a two-protein immunohistochemical classifier that performs well at predicting the absence of response to neoadjuvant treatment in rectal cancer.
2017-01-11 | GSE93375 | GEO
Project description:To investigate time-dependent changes the comprehensive gene expressions in colorectal normal and tumor surgical specimen within two hours. Both normal and tumor tissues were extracted at 0, 30, 60, 120 min after surgical removal in seven patients with locally advanced colorectal cancer and stabilized. RNA was extracted and calculated, time dependent changes of gene expression were examined by microarray data.
2013-09-11 | E-GEOD-50746 | biostudies-arrayexpress
Project description:We obtained fibroblast cultures from fresh surgical specimen ressected from patients with primary colorectal carcinoma: normal colonic fibroblasts (NCF=9) from the normal colonic mucosa at least 5-10cm from the surgical margin, carcinoma-associated fibroblasts from the primary tumor (CAF-PT=14) and carcinoma-associated fibroblasts (CAF-LM=11) from fresh surgical specimens of liver metastases. We identified 277 probes, in common between the three types of fibroblasts, whose expression level is sequentially deregulated according to cancer progression (NCF→CAF-PT→CAF-LM; fold change Log2 normalized expression>1.5 in each step). Prediction Analysis of Microarrays was applied to obtain a 25-gene signature that better characterizes each fibroblast class. The signature is able to classify patients carrying primary tumors according to prognosis. This fact was exploited to obtain a 19-gene signature (from the 277 deregulated probes) predicting recurrence with high accuracy in stage II/III colorectal cancer patients. Signature validation has been carried out in two independent datasets and in a meta-cohort of 336 stage II/III patients. Since the 25-gene signature was obtained regardless of gene expression data of tumor specimens or patient’s clinical data, the prognostic power of this signature provides strong evidence of the link between the tumor stroma and cancer progression. Furthermore, the 19-gene signature was able to identify low-risk patients with very high accuracy, especially relevant for those high-risk stage-II patients. We hybridised fibroblast RNA in Affymetrix GeneChip 1.0 st arrays
2013-05-10 | E-GEOD-46824 | biostudies-arrayexpress