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Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [ChIP-seq]

ABSTRACT: Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157090 | GEO | 2020/09/15

REPOSITORIES: GEO

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Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene expression programs in bladder cancer [RNA-seq]

Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.

2020-09-15 | GSE157089 | GEO

Gene expression data from FGFR3 induced mouse bladder tumors

Project description:Somatic mutations of the fibroblast growth factor receptor 3 (FGFR3) are one of the most frequent genetic alterations in bladder carcinomas. We report here that human-FGFR3-S249C expression in urothelial cells of transgenic mice induces low-grade papillary tumors presenting genomic instability and resembling human pTa urothelial tumors at the transcriptomic level. Mutated-FGFR3 expression levels impacted the incidence of tumor formation and could account for the tissue specificity of human mutated FGFR3-driven tumors restricted to epithelia presenting high normal expression levels of FGFR3.

2021-12-31 | GSE151888 | GEO

Expression data from normal urothelial cells with exogenous expression of mutant FGFR3

Project description:Activating mutations of FGFR3 are found in a high proportion of bladder tumours. The molecular consequences of FGFR3 mutation in urothelial cells and the mechanisms by which mutant FGFR3 may drive bladder tumourigenesis are largely unknown. We used expression arrays to identify downstream targets of mutant FGFR3 signalling in normal urothelial cells. TERT-immortalized normal urothelial cells stably transduced to express the most common FGFR3 mutation (S249C) were compared with control cells transduced with the empty vector (pFB).

2014-09-12 | E-GEOD-61352 | biostudies-arrayexpress

Expression data from normal urothelial cells with exogenous expression of mutant FGFR3

2014-09-12 | GSE61352 | GEO

RNA-seq profiling of upper tract urothelial carcinoma: bladder cancer consensus classification relevance, molecular heterogeneity and differential immune signatures

Project description:Analyses of large transcriptomics datasets of muscle-invasive bladder cancer (MIBC) has led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUC) are less known. Our objective was to determine the relevance of consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors.Subtype IHC markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16 and Ki67, MMR proteins, PD-L1 IHC were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3’RNA-seq, including with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression.Most of the 66 patients were men (77.3%), with pT1 (n=23, 34.8%) or pT2-4 stage UTUC (n=43, 65.2%). FGFR3 mutations and dMMR status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as Luminal papillary (LumP). Combining our consensus classification results to that of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUC, which was significantly higher than in MIBC. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular if FGFR3 mutated.

2023-10-10 | GSE244957 | GEO

Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implication on Adult Bladder Cancer

Project description:Bladder cancer is common in elderly men, and it is a highly mutated tumor with frequent TP53 and FGFR3 mutation. Young-onset bladder cancer (YBC) is extremely rare; therefore, its genomic characteristics are unknown and appropriate management strategy is yet to be defined. Through a nation-wide search for bladder cancer diagnosed at 20 years or younger, 29 cases of biopsy-proven YBCs were collected. Whole exome sequencing and RNA sequencing were performed on 21 and 11 cases, respectively, and the results were compared with those of adult bladder cancer (ABC) retrieved from public database. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had low mutation burden and less complex copy number alterations. Driver mutations were found in all cases. Common mutations included HRAS mutations (10 cases) with a preference in exon 5 and FGFR3 gene fusions (7 cases) with various partner genes, which occurred in a mutually exclusive manner. Other alterations included KRAS mutations (2 cases), arm-level deletion of chromosomes 4p and 10q (1 case), and ERCC2 mutation (1 case). TP53 and FGFR3 point mutations were not found. The gene expression profiles of YBC corresponded to those of the good prognostic group of ABC. No YBC cases had progressed to muscle-invasive tumor during follow-up. In addition, ABCs with YBC-like mutations also showed no progression to muscle-invasive tumor. In conclusion, YBC had distinct driver genetic alterations such as HRAS mutation and FGFR3 gene fusion and showed good prognosis. YBCs and ABCs with YBC-like mutations may be managed with less aggressive surveillance.

2020-03-30 | GSE133192 | GEO

Gene expression data from MGHU3 bladder cancer cells (FGFR3-Y375C) treated with TAK1 siRNA and/or PD173074

Project description:The NFM-NM-:B transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFM-NM-:B activation. A critical mediator of NFM-NM-:B activity is TGFM-NM-2-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and direct target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes which regulate NFM-NM-:B signaling, and promote both NFM-NM-:B transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFM-NM-:B activation. A total of 12 samples of MGHU3 (Y375C) mutant FGFR3 bladder cancer cells (a kind gift from Dr. Margaret Knowles (University of Leeds, Leeds, UK)) were used for array-based gene expression analysis. 3 replicates of each condition: Control siRNA, Control siRNA + PD173074, TAK1 siRNA, and TAK1 siRNA + PD173074.

2013-11-19 | E-GEOD-52452 | biostudies-arrayexpress

FGFR3-shRNA induced transcriptional changes in RT112 bladder cancer cells

Project description:Aberrant activation of FGFR3 via overexpression or mutation is a frequent feature of bladder cancer; however, its molecular and cellular consequences and functional relevance to carcinogenesis are not well understood. In this study with a bladder carcinoma cell line expressing inducible FGFR3 shRNAs, we sought to identiy transcriptional targets of FGFR3 and investigate their contribution to bladder cancer development. Bladder cancer cell line RT112 was transduced with a doxycycline-inducible control EGFP shRNA or three independent FGFR3 shRNAs, designated FGFR3 shRNA 2-4, FGFR3 shRNA 4-1 and FGFR3 shRNA 6-16. These four cell lines were treated with or without doxycycline for 48 hr to deplete FGFR3 protein prior to the isolation of mRNA for microarray analysis. Genes that were differentially expressed after doxycycline induction in all three FGFR3-depleted cell lines but not in the control cell line were considered potential FGFR3-regulated genes. Each treatment group was run in triplcates, and there are 24 samples.

2012-11-07 | E-GEOD-41035 | biostudies-arrayexpress

The UBC-40 Urothelial Bladder Cancer Cell Line Index [copy number variation]

Project description:This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing. Copy Number Variations were assessed in 45 bladder cell lines, included in the UBC-40 Urothelial Bladder Cell Line Index, with Human1M-Duov3 DNA Analysis BeadChip platform

2015-06-19 | E-GEOD-64572 | biostudies-arrayexpress

The UBC-40 Urothelial Bladder Cancer Cell Line Index [gene expression]

Project description:This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing. Expression levels were assessed in 20 bladder cell lines, included in the UBC-40 Urothelial Bladder Cell Line Index, with Affymetrix U133 array platform

2015-06-19 | E-GEOD-64279 | biostudies-arrayexpress

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