Downregulation of the Coiled-Coil Domain Containing 80 and Its Perspective Mechanisms in Ovarian Carcinoma: A Comprehensive Study

Introduction. We aimed to explore the downregulation of the coiled-coil domain containing 80 (CCDC80) and its underlying molecular mechanisms in ovarian carcinoma (OVCA). Materials/Methods. Immunohistochemical staining was performed to confirm the expression status of CCDC80 protein. Combining the data from in-house tissue microarrays and high-throughput datasets, we identified the expression level of CCDC80 in OVCA. We utilized cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm and single-sample gene set enrichment analysis (ssGSEA) to explore the relationship between CCDC80 and the tumor microenvironment (TME) landscape in OVCA. Pathway enrichment, function annotation, and transcription factor (TFs) exploration were conducted to study the latent molecular mechanisms. Moreover, the cell line data in the Genomics of Drug Sensitivity in Cancer (GDSC) database was used to discover the relationship between CCDC80 and drug sensitivity. Results. An integrated standard mean difference (SMD) of −0.919 (95% CI: −1.515–0.324, P = 0.002 ) identified the downregulation of CCDC80 in OVCA based on 1048 samples, and the sROC ( AUC = 0.76 ) showed a moderate discriminatory ability of CCDC80 in OVCA. The fraction of infiltrating naive B cells showed significant differences between the high- and low-CCDC80 expression groups. Also, CCDC80-related genes are enriched in the Ras signaling pathway and metabolic of lipid. Nuclear receptor subfamily three group C member 1 (NR3C1) may be an upstream TF of CCDC80, and CCDC80 may be related to the sensitivity of mitocycin C and nilotinib. Conclusion. CCDC80 was downregulated in OVCA and may play a role as a tumor suppressor in OVCA.

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Prognostic Value of BTNL9 Combined with Genes of Proteasome and Ubiquitin System in Pancreatic Cancer

10.21203/rs.3.rs-955285/v1 ◽

2021 ◽

Author(s):

Ke Xu ◽

Qingfan Mo ◽

Bo Liu ◽

Rongfei Huang ◽

Wei Zhou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Prognostic Factors ◽

Prognostic Value ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

High Expression ◽

Immune Checkpoints ◽

Prognostic Prediction ◽

The Relationship

Abstract Background: An accurate prognostic prediction can improve the individualized management of patients with pancreatic cancer (PC), and the exploration of biomarkers with prognostic value for clinical practice is the prerequisite of the work. Butyrophilin-Like 9 (BTNL9) has recently been found to function as a tumor suppressor gene in a variety of malignancies and has the potency to serve as a prognostic biomarker. Our aim was to explore the relationship between BTNL9 expression and the prognosis of PC, and to unearth its upstream and downstream molecular mechanisms. Methods: The RNA expression of BTNL9 was analyzed in 5 datasets from Gene Expression Omnibus (GEO) database. The protein expression of BTNL9 was detected by immunohistochemistry in a cohort including 42 PC patients. The relationship between BTNL9 expression and prognosis was analyzed by survival and prognostic factors analysis. Online database and Gene Set Enrichment Analysis (GSEA) were used to explore the upstream and downstream molecular mechanisms of BTNL9. Correlation analysis and CIBERSORT were applied to investigate the relationship between BTNL9 and tumor immunology.Results: In multiple datasets and our cohort, BTNL9 expression was decreased in PC tissues. Patients with high expression of BTNL9 had a better prognosis. BTNL9, age and N stage were identified as the independent prognostic factors of PC. BTNL9 was predicted to be down-regulated by hsa-miR-1910-5p, and it may be involved in the proteasome and PC signaling pathway. Interestingly, genes of proteasome (PSMD2, PSMD7 and PMSD14) and deubiquitin system (USP20, USP27X and USP30) combined BTNL9 could improve the prognostic prediction of PC. In addition, the expression of BTNL9 correlates with the expression of immune checkpoints and influences the infiltration of tumor immune cells. Conclusions: BTNL9 can serve as a prognostic marker of PC, and high expression of BTNL9 was generally associated with better prognosis. Combined the expression of BTNL9 and the expression of PSMD2, PSMD7, PMSD14, USP20, USP27X and USP30 can more accurately analyze the prognosis of patients with PC.

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Screen Key Genes Associated with Distraction-Induced Osteogenesis of Stem Cells Using Bioinformatics Methods

International Journal of Molecular Sciences ◽

10.3390/ijms22126505 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6505

Author(s):

Jishizhan Chen ◽

Jia Hua ◽

Wenhui Song

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Negative Control ◽

Gene Set Enrichment Analysis ◽

Venn Diagram ◽

Hub Genes ◽

Protein Protein Interaction ◽

Two Samples ◽

Key Genes

Applying mesenchymal stem cells (MSCs), together with the distraction osteogenesis (DO) process, displayed enhanced bone quality and shorter treatment periods. The DO guides the differentiation of MSCs by providing mechanical clues. However, the underlying key genes and pathways are largely unknown. The aim of this study was to screen and identify hub genes involved in distraction-induced osteogenesis of MSCs and potential molecular mechanisms. Material and Methods: The datasets were downloaded from the ArrayExpress database. Three samples of negative control and two samples subjected to 5% cyclic sinusoidal distraction at 0.25 Hz for 6 h were selected for screening differentially expressed genes (DEGs) and then analysed via bioinformatics methods. The Gene Ontology (GO) terms and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment were investigated. The protein–protein interaction (PPI) network was visualised through the Cytoscape software. Gene set enrichment analysis (GSEA) was conducted to verify the enrichment of a self-defined osteogenic gene sets collection and identify osteogenic hub genes. Results: Three hub genes (IL6, MMP2, and EP300) that were highly associated with distraction-induced osteogenesis of MSCs were identified via the Venn diagram. These hub genes could provide a new understanding of distraction-induced osteogenic differentiation of MSCs and serve as potential gene targets for optimising DO via targeted therapies.

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In Silico Identification of Contradictory Role of ADAMTS5 in Hepatocellular Carcinoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033820986826 ◽

2021 ◽

Vol 20 ◽

pp. 153303382098682

Author(s):

Zhipeng Zhu ◽

Jiuhua Xu ◽

Xiaofang Wu ◽

Sihao Lin ◽

Lulu Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Subgroup Analysis ◽

Prognostic Value ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Clinicopathological Parameters ◽

Free Survival ◽

Cox Regression Analysis ◽

The Impact

Background: ADAMTS5 has different roles in multiple types of cancers and participates in various molecular mechanisms. However, the prognostic value of ADAMTS5 in patients with hepatocellular carcinoma (HCC) still remains unclear. We carried the study to evaluate the prognostic value and identified underlying molecular mechanisms in HCC. Methods: Firstly, the association of ADAMTS5 expression and clinicopathological parameters was evaluated by in GSE14520. Next, ADAMTS5 expression in HCC was performed using GSE14520, GSE36376, GSE76427 and The Cancer Genome Atlas (TCGA) profile. Furthermore, Kaplan-Meier analysis, Univariate and Multivariate Cox regression analysis, subgroup analysis was performed to evaluate the prognostic value of ADAMTS5 in HCC. Finally, GO enrichment analysis, gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were performed to revealed underlying molecular mechanisms. Result: The expression of ADAMTS5 was positively correlated with the development of HCC. Next, high ADAMTS5 expression was significantly associated with poorer survival (all P < 0.05) and the impact of ADAMTS5 on all overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), disease specific survival (DSS) and progression free interval (PFI) was specific for HCC among other 29 cancer types. Subgroup analysis showed that ADAMTS5 overexpression was significantly associated with poorer OS in patients with HCC. Finally, ADAMTS5 might participate in the status conversion from metabolic-dominant to extracellular matrix-dominant, and the activation of ECM-related biological process might contribute to high higher mortality risk for patients with HCC. Conclusion: ADAMTS5 may play an important role in the progression of HCC, and may be considered as a novel and effective biomarker for predicting prognosis for patients with HCC.

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The Analysis of PTPN6 for Bladder Cancer: An Exploratory Study Based on TCGA

Disease Markers ◽

10.1155/2020/4312629 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Chengquan Shen ◽

Jing Liu ◽

Jirong Wang ◽

Xiaokun Yang ◽

Haitao Niu ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

Survival Analysis ◽

Prognostic Value ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Gene Set Enrichment Analysis ◽

Expression Level ◽

Pathologic Features ◽

The Relationship

PTPN6 (protein tyrosine phosphatase nonreceptor type 6), a tyrosine phosphatase, is known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Previous studies have demonstrated that PTPN6 expression is relatively elevated in several malignancies. However, the role of PTPN6 in bladder cancer (BC) remains unclear. The purpose of this study was to explore the prognostic value of PTPN6 in BC. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify the expression level of PTPN6 in BC. The relationship between clinical pathologic features and PTPN6 were analyzed with the Wilcoxon signed-rank test. The prognostic and predictive value of PTPN6 was evaluated by survival analysis and nomogram. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential molecular mechanisms of PTPN6 in BC. Finally, Tumor Immune Estimation Resource (TIMER) was applied to investigate the relationship between PTPN6 and immune cell infiltration in the tumor microenvironment. Results indicated that PTPN6 was overexpressed in BC tissues compared with normal bladder tissues and was significantly correlated with grade, stage, T, and N. Survival analysis showed that low expression of PTPN6 was significantly related to the poor overall survival (OS) in BC patients. Coexpression analysis showed that PTPN6 and TNFRSF14 (Tumor necrosis factor receptor superfamily member 14) have a close correlation in BC. GSEA showed that multiple cancer-associated signaling pathways are differentially enriched in the PTPN6 high expression phenotype. Moreover, the expression level of PTPN6 was positively associated with the infiltration of B cells, CD4+T cells, dendritic cells, and neutrophils and negatively associated with CD8+ T cells and macrophages in BC. In conclusion, we identified that PTPN6 may be a novel prognostic biomarker in BC based on the TCGA database. Further clinical trials are needed to confirm our observations and mechanisms underlying the prognostic value of PTPN6 in BC also deserve further experimental exploration.

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Transcriptomic Analysis of the Differential Nephrotoxicity of Diverse Brominated Flame Retardants in Rat and Human Renal Cells

International Journal of Molecular Sciences ◽

10.3390/ijms221810044 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10044

Author(s):

Lillie Marie A. Barnett ◽

Naomi E. Kramer ◽

Amanda N. Buerger ◽

Deirdre H. Love ◽

Joseph H. Bisesi ◽

...

Keyword(s):

Cell Lines ◽

Flame Retardants ◽

Molecular Mechanisms ◽

Annexin V ◽

Enrichment Analysis ◽

Brominated Flame Retardants ◽

Human Cells ◽

Gene Set Enrichment Analysis ◽

Coagulation Cascade ◽

Transcriptional Changes

Brominated flame retardants (BFRs) are environmentally persistent, are detected in humans, and some have been banned due to their potential toxicity. BFRs are developmental neurotoxicants and endocrine disruptors; however, few studies have explored their potential nephrotoxicity. We addressed this gap in the literature by determining the toxicity of three different BFRs (tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD), and tetrabromodiphenyl ether (BDE-47)) in rat (NRK 52E) and human (HK-2 and RPTEC) tubular epithelial cells. All compounds induced time- and concentration-dependent toxicity based on decreases in MTT staining and changes in cell and nuclear morphology. The toxicity of BFRs was chemical- and cell-dependent, and human cells were more susceptible to all three BFRs based on IC50s after 48 h exposure. BFRs also had chemical- and cell-dependent effects on apoptosis as measured by increases in annexin V and PI staining. The molecular mechanisms mediating this toxicity were investigated using RNA sequencing. Principal components analysis supported the hypothesis that BFRs induce different transcriptional changes in rat and human cells. Furthermore, BFRs only shared nine differentially expressed genes in rat cells and five in human cells. Gene set enrichment analysis demonstrated chemical- and cell-dependent effects; however, some commonalities were also observed. Namely, gene sets associated with extracellular matrix turnover, the coagulation cascade, and the SNS-related adrenal cortex response were enriched across all cell lines and BFR treatments. Taken together, these data support the hypothesis that BFRs induce differential toxicity in rat and human renal cell lines that is mediated by differential changes in gene expression.

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Gene Expression Profile of Active HE4 Stimulation in Epithelial Ovarian Cancer Cells: Microarray Study and Comprehensive Bioinformatics Analysis

10.21203/rs.3.rs-46014/v1 ◽

2020 ◽

Author(s):

Liancheng Zhu ◽

Mingzi Tan ◽

Haoya Xu ◽

Bei Lin

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Clinical Significance ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Coexpression Analysis ◽

Pathway Enrichment

Abstract Background.Human Epididymis Protein 4 (HE4) is a novel serum biomarker for diagnosis of epithelial ovarian cancer (EOC) with high specificity and sensitivity compared with CA125, and the increasing researches have been carried out on its roles in promoting carcinogenesis and chemoresistance in EOC in recent years, however, its underlying molecular mechanisms remain poorly understood. The aim of this study was to elucidate the molecular mechanisms of HE4 stimulation and to identify the key genes and pathways mediating carcinogenesis in EOC using microarray and bioinformatics analysis.Methods. We established a stable HE4-silence ES-2 ovarian cancer cell line labeled as “S”, and its active HE4 protein stimulated cells labeled as “S4”. Human whole genome microarray analysis was used to identify deferentially expressed genes (DEGs) from triplicate samples of S4 and S cells. “clusterProfiler” package in R, DAVID, Metascape, and Gene Set Enrichment Analysis (GSEA) were used to perform gene ontology (GO) and pathway enrichment analysis, and cBioPortal for WFDC2 coexpression analysis. GEO dataset (GSE51088) and quantitative real-time polymerase chain reaction (qRT-PCR) was applied for validation. The protein–protein interaction (PPI) network and modular analyses were performed using Metascape and Cytoscape. Results.In total, 713 DEGs were found (164 up regulated and 549 down regulated) and further analyzed by GO, pathway enrichment and PPI analyses. We found that MAPK pathway accounted for a significant portion of the enriched terms. WFDC2 coexpression analysis revealed ten WFDC2 coexpressed genes (TMEM220A, SEC23A, FRMD6, PMP22, APBB2, DNAJB4, ERLIN1, ZEB1, RAB6B, and PLEKHF1) that were also dramatically changed in S4 cells and validated by dataset GSE51088. Kaplan–Meier survival statistics revealed clinical significance for all of the 10 target genes. Finally, PPI was constructed, sixteen hub genes and eight molecular complex detections (MCODEs) were identified, the seeds of five most significant MCODEs were subjected to GO and KEGG enrichment analysis and their clinical significance was evaluated.Conclusions.By applying microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of active HE4 stimulation in EOC cells. We offered several possible mechanisms and identified therapeutic and prognostic targets of HE4 in EOC.

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Gene expression profiles following active HE4 stimulation in epithelial ovarian cancer cells: microarray study and comprehensive bioinformatics analysis

10.21203/rs.3.rs-100248/v1 ◽

2020 ◽

Author(s):

Liancheng Zhu ◽

Mingzi Tan ◽

Haoya Xu ◽

Bei Lin

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Molecular Mechanisms ◽

Bioinformatics Analysis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Ppi Network ◽

Coexpression Analysis ◽

Pathway Enrichment

Abstract Background: Human epididymis protein 4 (HE4) is a novel serum biomarker for diagnosing epithelial ovarian cancer (EOC) with high specificity and sensitivity, compared with CA125. Recent studies have focused on the roles of HE4 in promoting carcinogenesis and chemoresistance in EOC; however, the molecular mechanisms underlying its action remain poorly understood. This study was conducted to determine the molecular mechanisms underlying HE4 stimulation and identifying key genes and pathways mediating carcinogenesis in EOC by microarray and bioinformatics analysis.Methods: We established a stable HE4-silenced ES-2 ovarian cancer cell line labeled as “S”; the S cells were stimulated with the active HE4 protein, yielding cells labeled as “S4”. Human whole-genome microarray analysis was used to identify differentially expressed genes (DEGs) in S4 and S cells. The “clusterProfiler” package in R, DAVID, Metascape, and Gene Set Enrichment Analysis were used to perform gene ontology (GO) and pathway enrichment analysis, and cBioPortal was used for WFDC2 coexpression analysis. The GEO dataset (GSE51088) and quantitative real-time polymerase chain reaction were used to validate the results. Protein–protein interaction (PPI) network and modular analyses were performed using Metascape and Cytoscape, respectively. Results: In total, 713 DEGs were identified (164 upregulated and 549 downregulated) and further analyzed by GO, pathway enrichment, and PPI analyses. We found that the MAPK pathway accounted for a significant large number of the enriched terms. WFDC2 coexpression analysis revealed ten WFDC2-coexpressed genes (TMEM220A, SEC23A, FRMD6, PMP22, APBB2, DNAJB4, ERLIN1, ZEB1, RAB6B, and PLEKHF1) whose expression levels were dramatically altered in S4 cells; this was validated using the GSE51088 dataset. Kaplan–Meier survival statistics revealed that all 10 target genes were clinically significant. Finally, in the PPI network, 16 hub genes and 8 molecular complex detections (MCODEs) were identified; the seeds of the five most significant MCODEs were subjected to GO and KEGG enrichment analyses and their clinical relevance was evaluated.Conclusions: Through microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network following active HE4 stimulation in EOC cells. We proposed several possible mechanisms underlying the action of HE4 and identified the therapeutic and prognostic targets of HE4 in EOC.

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Increased Expression of LYNX1 in Ovarian Serous Cystadenocarcinoma Predicts Poor Prognosis

BioMed Research International ◽

10.1155/2020/1392674 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Hui Liu ◽

Ao Wang ◽

Yushan Ma

Keyword(s):

Ovarian Cancer ◽

Univariate Analysis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Gene Set Enrichment ◽

Gene Set ◽

Serous Cystadenocarcinoma ◽

Kaplan Meier ◽

Pathologic Features ◽

The Relationship

Few studies have reported the function of LYNX1 in ovarian cancer. We retrieved LYNX1 gene expression data and clinical information of 376 patients with ovarian cancer from The Cancer Genome Atlas (TCGA) project website. Wilcoxon signed-rank test and logistic regression were used to analyze the relationship between clinical pathologic features and LYNX1 expression. The Kaplan–Meier method was used to draw survival curves of patients, and Cox regression was used to calculate the relationship between LYNX1 expression and survival rate or the clinicopathological characteristics of the patients. Gene set enrichment analysis (GSEA) was performed, and the correlation between LYNX1 expression and cancer immune infiltrates was investigated via single sample gene set enrichment analysis (ssGSEA). High LYNX1 expression in ovarian serous cystadenocarcinoma (OVs) was associated with tumor residual disease (RD). In Kaplan–Meier survival analysis, patients with OVs who also displayed high LYNX1 expression had decreased overall survival (OS) and disease-specific survival (DSS) than those with low LYNX1 expression. Univariate analysis also supported that patients with high LYNX1 expression had lower OS than those with low LYNX1 expression. LYNX1 expression has the potential to be a prognostic molecular marker of poor survival in OVs.

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Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00438.2012 ◽

2013 ◽

Vol 305 (1) ◽

pp. G58-G65 ◽

Cited By ~ 20

Author(s):

Yu Fang ◽

Hao Chen ◽

Yuhui Hu ◽

Zorka Djukic ◽

Whitney Tevebaugh ◽

...

Keyword(s):

Gastroesophageal Reflux ◽

Barrier Function ◽

Molecular Mechanisms ◽

Target Genes ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Esophageal Epithelium ◽

Gene Set Enrichment ◽

Gene Sets ◽

Epithelial Resistance

The barrier function of the esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. To develop novel therapies, it is critical to understand the molecular mechanisms whereby contact with a refluxate impairs esophageal barrier function. In this study, surgical models of duodenal and mixed reflux were developed in mice. Mouse esophageal epithelium was analyzed by gene microarray. Gene set enrichment analysis showed upregulation of inflammation-related gene sets and the NF-κB pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-κB target genes. Overexpression of NF-κB subunits (p50 and p65) and NF-κB target genes (matrix metalloproteinases-3 and -9, IL-1β, IL-6, and IL-8) confirmed activation of the NF-κB pathway in the esophageal epithelium. In addition, real-time PCR, Western blotting, and immunohistochemical staining also showed downregulation and mislocalization of claudins-1 and -4. In a second animal experiment, treatment with an NF-κB inhibitor, BAY 11-7085 (20 mg·kg−1·day−1 ip for 10 days), counteracted the effects of duodenal and mixed reflux on epithelial resistance and NF-κB-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice and that targeting the NF-κB pathway may strengthen esophageal barrier function against reflux.

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Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14544 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14544-e14544

Author(s):

Eva Budinska ◽

Jenny Wilding ◽

Vlad Calin Popovici ◽

Edoardo Missiaglia ◽

Arnaud Roth ◽

...

Keyword(s):

Gene Expression ◽

Cell Line ◽

Clinical Significance ◽

Cell Lines ◽

Drug Response ◽

Drug Sensitivity ◽

Expression Profiles ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

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