A combination of extracellular matrix- and interferon-associated signatures identifies high-grade breast cancers with poor prognosis.
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ABSTRACT:
SUBMITTER: Lecchi M
PROVIDER: S-EPMC8096783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe IGFBP family of insulin-like growth factor binding proteins has important biological functions in the organism. However, the role of the IGFBP family in low-grade glioma (LGG) has not been fully explored.MethodsWe validated the clinical value of the IGFBP family using RNA-seq and clinical data of LGG in the TCGA and constructed an IGFBPScore using LASSO-regression analysis for prognosis prediction, subtype determination, and treatment sensitivity determination. Subsequently, we explored the role of the IGFBP family in the development of LGG using PanCanAtlas data.ResultsOur results suggest that most IGFBP family members were aberrantly expressed and were strongly associated with poor prognosis in LGG. By constructing an IGFBPScore representing the IGFBP family, we found that tumor samples with a high IGFBPScore had a glioblastoma-like mutation pattern characterized by IDH1wt, EGFRmut, PTENmut, and NF1mut with hypo-methylation and glioma stem cell (GSC) diversity. In contrast, the low IGFBPScore group was characterized by IDH1mut accompanied by TP53mut, CICmut, and ATRXmut, and had hyper-methylation status as well as the GSC restriction. Additionally, the high-IGFBPScore group had a high inflammation phenotype with increased immune antigenicity and increased infiltration of immune molecules and cells, as well as a high extracellular matrix phenotype and enhanced multiple metabolic pathways compared with the immune-quiet phenotype of the low-IGFBPScore group, which was strongly associated with poor prognosis.ConclusionOur study provides a summary analysis and a theoretical basis for the biological role and clinical value of the IGFBP family in LGG, providing an important therapeutic target for LGG.
| S-EPMC9381844 | biostudies-literature
Project description:BackgroundColorectal cancer is the third most frequently diagnosed cancer and the third cause of cancer deaths in the United States. Despite the fact that tumor cell-intrinsic mechanisms controlling colorectal carcinogenesis have been identified, novel prognostic and diagnostic tools as well as novel therapeutic strategies are still needed to monitor and target colon cancer progression. We and others have previously shown, using mouse models, that the extracellular matrix (ECM), a major component of the tumor microenvironment, is an important contributor to tumor progression. In order to identify candidate biomarkers, we sought to define ECM signatures of metastatic colorectal cancers and their metastases to the liver.MethodsWe have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver in comparison with normal colon and liver samples.ResultsWe show that robust signatures of ECM proteins characteristic of each tissue, normal and malignant, can be defined using relatively small samples from small numbers of patients. Comparisons with gene expression data from larger cohorts of patients confirm the association of subsets of the proteins identified by proteomic analysis with tumor progression and metastasis.ConclusionsThe ECM protein signatures of metastatic primary colon carcinomas and metastases to liver defined in this study, offer promise for development of diagnostic and prognostic signatures of metastatic potential of colon tumors. The ECM proteins defined here represent candidate serological or tissue biomarkers and potential targets for imaging of occult metastases and residual or recurrent tumors and conceivably for therapies. Furthermore, the methods described here can be applied to other tumor types and can be used to investigate other questions such as the role of ECM in resistance to therapy.
| S-EPMC4223627 | biostudies-literature
Project description:Purpose: Multiple studies from last decades have shown that the microenvironment of carcinomas plays an important role in the initiation, progression and metastasis of cancer. Our group has previously identified novel cancer stroma gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of two tumors of fibroblasts as surrogates for physiologic stromal expression patterns. The aim of this study is to find additional new types of tumor stroma gene expression patterns. Results: 53 tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the elastofibroma (EF) and fibroma of tendon sheath (FOTS) gene signatures demonstrated robust outcome results for survival in the four breast cancer datasets. The EF signature positive breast cancers (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature positive breast cancers (11-35% of the cohort) had a worse outcome. The combined stromal signatures of EF, FOTS, and our previously identified DTF, and CSF1 signatures characterize, in part, the stromal expression profile for the tumor microenvironment for between 74%-90% of all breast cancers. Conclusions: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Gene expression profiling by 3SEQ was performed on 8 additional types of fibrous tumors, to identify different fibrous tumor specific gene expression signatures. We then determined the significance of the fibrous tumor gene signatures in four publically available breast cancer datasets (GSE1456, GSE4922, GSE3494, NKI Dataset).
| S-ECPF-GEOD-42948 | biostudies-other
Project description:Extracellular matrix interactions play essential roles in normal physiology and many pathological processes. Here, we report a novel screening platform capable of measuring phenotypic responses to combinations of ECM molecules. While the importance of ECM interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Using a genetic mouse model of lung adenocarcinoma, we measured the ECM-dependent adhesion of tumor-derived cells. Hierarchical clustering of adhesion profiles generated using this platform differentially segregated metastatic cell lines from primary tumor lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8, or laminin. These interactions appear to be mediated in part by α3β1 integrin both in vitro and in vivo. We show that these galectins also correlate with human disease at both a transcriptional and histological level. Thus, our in vitro platform allowed us to interrogate the interactions of metastatic cells with their surrounding environment, and identified ECM and integrin interactions that could lead to therapeutic targets for metastasis prevention. Cell lines derived from murine lung primary adenocarcinomas and their metastases (Winslow et al., 2011 Nature 473:101-104)
2012-10-11 | E-GEOD-40222 | biostudies-arrayexpress
Project description:Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association of CVH metrics with the circulating lipid profile of a population-based cohort. Serum sphingolipid and phospholipid species were extracted from 461 patients of the randomly selected prospective Kardiovize study based on Brno, Czech Republic. Lipids species were measured by a hyphenated mass spectrometry technique, and were associated with poor CVH scores, as defined by the American Heart Association. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) species were significantly lower in ideal and intermediate scores of health dietary metric, blood pressure, total cholesterol and blood fasting glucose compared to poor scores. Current smokers presented higher levels of PC, PE and LPE individual species compared to non-smokers. Ceramide (Cer) d18:1/14:0 was altered in poor blood pressure, total cholesterol and fasting blood glucose metrics. Poor cardiovascular health metric is associated with a specific phospho- and sphingolipid pattern. Circulatory lipid profiling is a potential biomarker to refine cardiovascular health status in primary prevention strategies.
| S-EPMC8624456 | biostudies-literature
Project description:BackgroundRas suppressor 1 (RSU1), a highly conserved protein, plays an important role in actin cytoskeleton remodeling and cell-extracellular matrix adhesion. Aberration of RSU1 activity can cause changes in cell adhesion and migration, thereby enhancing tumor proliferation and metastasis. However, the correlation between RSU1 and gastrointestinal cancers (GICs), as well as its prognostic role related to tumor-infiltrating immune cells (TIICs) remains unclear.AimTo shows RSU1 plays a potential promoting role in facilitating tumor immune escape in GIC.MethodsDifferential expression of RSU1 in different tumors and their corresponding normal tissues was evaluated by exploring the Gene Expression Profiling Interactive Analysis (GEPIA) dataset. The correlation between RSU1 expression and prognosis of GIC cancer patients was evaluated by Kaplan-Meier plotter. Then, RSU1-correlated genes were screened and functionally characterized via enrichment analysis. The correlation between RSU1 and TIICs was further characterized using the Tumor Immune Estimation Resource (TIMER). In addition, the correlation between RSU1 and immune cell surface molecules was also analyzed by TIMER.ResultsHigh RSU1 expression was associated with poor overall survival of gastric cancer patients, exhibiting a hazard ratio (HR) = 1.36, first progression HR = 1.53, and post progression survival HR = 1.6. Specifically, high RSU1 Levels were associated with prognosis of gastric cancer in females, T4 and N3 stages, and Her-2-negative subtypes. Regarding immune-infiltrating cells, RSU1 expression level was positively correlated with infiltration of CD4+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in colorectal adenocarcinoma and stomach adenocarcinoma. RSU1 expression was also predicted to be strongly correlated with immune marker sets in M2 macrophage, DCs and T cell exhaustion in GICs.ConclusionIn gastrointestinal cancers, RSU1 is increased in tumor tissues, and predicts poor survival of patients. Increased RSU1 may be involved in promoting macrophage polarization, DC infiltration, and T cell exhaustion, inducing tumor immune escape and the development of tumors in GICs. We suggest that RSU1 is a promising prognostic biomarker reflecting immune infiltration level of GICs, as well as a potential therapeutic target for precision treatment through improving the immune response.
| S-EPMC10523239 | biostudies-literature
Project description:IntroductionRAD21 is a component of the cohesin complex, which is essential for chromosome segregation and error-free DNA repair. We assessed its prognostic and predictive power in a cohort of in situ and invasive breast cancers, and its effect on chemosensitivity in vitro.MethodsRAD21 immunohistochemistry was performed on 345 invasive and 60 pure in situ carcinomas. Integrated genomic and transcriptomic analyses were performed on a further 48 grade 3 invasive cancers. Chemosensitivity was assessed in breast cancer cell lines with an engineered spectrum of RAD21 expression.ResultsRAD21 expression correlated with early relapse in all patients (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.06 to 2.86, P = 0.029). This was due to the effect of grade 3 tumors (but not grade 1 or 2) in which RAD21 expression correlated with early relapse in luminal (P = 0.040), basal (P = 0.018) and HER2 (P = 0.039) groups. In patients treated with chemotherapy, RAD21 expression was associated with shorter overall survival (P = 0.020). RAD21 mRNA expression correlated with DNA copy number, with amplification present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 grade 3 cancers. Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines. Knockdown of RAD21 in the MDA-MB-231 breast cancer cell line significantly enhanced sensitivity to cyclophosphamide, 5-fluorouracil and etoposide. The findings for the former two drugs recapitulated the clinical findings.ConclusionsRAD21 expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. RAD21 may be a novel therapeutic target.
| S-EPMC3109576 | biostudies-literature
Project description:TRPS1 is aberrantly expressed in a variety of tumors, including breast, prostate, and gastric cancers, and is strongly associated with tumorigenesis or prognosis. However, the role of TRPS1 in high grade serous ovarian carcinoma (HGSC) is unknown. We investigated the relationship between TRPS1 expression and clinicopathology in HGSC patients. The tumor-related regulatory mechanisms of TRPS1 was explored through in vivo and vitro experiments. The results showed that TRPS1 was highly expressed in HGSC compared to normal tissues. It was also linked to the cell proliferation index Ki67 and poor prognosis. In vivo experiments showed that knockdown of TRPS1 could inhibit tumor growth. In vitro experiments, knockdown of TRPS1 inhibited the proliferation of ovarian cancer cells. TRPS1 exerted its regulatory role as a transcription factor, binding to the PSAT1 promoter and promoting the expression of PSAT1 gene. Meanwhile, PSAT1 was positively correlated with CCND1 expression. These results suggest that TRPS1 affects HGSC proliferation and cell cycle by regulating PSAT1 and thus CCND1 expression.
2023-12-11 | GSE249935 | GEO
Project description:Extracellular matrix interactions have essential roles in normal physiology and many pathological processes. Although the importance of extracellular matrix interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel-screening platform capable of measuring phenotypic responses to combinations of extracellular matrix molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the extracellular matrix-dependent adhesion of tumour-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumour lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by ?3?1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets.
| S-EPMC3794716 | biostudies-literature
Project description:BackgroundA major obstacle to the development of personalized therapies for gastric cancer (GC) is the prevalent heterogeneity at the intra-tumor, intra-patient, and inter-patient levels. Although the pathological stage and histological subtype diagnosis can approximately predict prognosis, GC heterogeneity is rarely considered. The extracellular matrix (ECM), a major component of the tumor microenvironment (TME), extensively interacts with tumor and immune cells, providing a possible proxy to investigate GC heterogeneity. However, ECM consists of numerous protein components, and there are no suitable models to screen ECM-related genes contributing to tumor growth and prognosis. We constructed patient-derived tumor xenograft (PDTX) models to obtain robust ECM-related transcriptomic signatures to improve GC prognosis prediction and therapy design.MethodsOne hundred twenty two primary GC tumor tissues were collected to construct PDTX models. The tumorigenesis rate and its relationship with GC prognosis were investigated. Transcriptome profiling was performed for PDTX-originating tumors, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to extract prognostic ECM signatures and establish PDTX tumorigenicity-related gene (PTG) scores. The predictive ability of the PTG score was validated using two independent cohorts. Finally, we combined PTG score, age, and pathological stage information to establish a robust nomogram for GC prognosis prediction.ResultsWe found that PDTX tumorigenicity indicated a poor prognosis in patients with GC, even at the same pathological stage. Transcriptome profiling of PDTX-originating GC tissues and corresponding normal controls identified 383 differentially expressed genes, with enrichment of ECM-related genes. A robust prognosis prediction model using the PTG score showed robust performance in two validation cohorts. A high PTG score was associated with elevated M2 polarized macrophage and cancer-associated fibroblast infiltration. Finally, combining the PTG score with age and TNM stage resulted in a more effective prognostic model than age or TNM stage alone.ConclusionsWe found that ECM-related signatures may contribute to PDTX tumorigenesis and indicate a poor prognosis in GC. A feasible survival prediction model was built based on the PTG score, which was associated with immune cell infiltration. Together with patient ages and pathological TNM stages, PTG score could be a new approach for GC prognosis prediction.
| S-EPMC10510236 | biostudies-literature