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FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation

ABSTRACT: FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation

PROVIDER: PRJNA1016348 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26051048_1.fastq.gz	Fastqsanger.gz
	SRR26051048_2.fastq.gz	Fastqsanger.gz
	SRR26051049_1.fastq.gz	Fastqsanger.gz
	SRR26051049_2.fastq.gz	Fastqsanger.gz
	SRR26051050_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

FGFR3 alterations in bladder cancer stimulate serine synthesis to induce immune-inert macrophages that suppress T-cell recruitment and activation

Project description:Metabolic reprogramming of bladder cancer cells driven by mutant FGFR3 increases serine synthesis that suppresses macrophage immunostimulatory functions to generate an immunosuppressive tumor microenvironment, which can be overcome by targeting PI3K.

2023-09-18 | GSE243093 | GEO

FGFR3 Alterations in Bladder Cancer Stimulate Serine Synthesis to Induce Immune-Inert Macrophages That Suppress T-cell Recruitment and Activation.

Project description:FGFR3 alterations are common in patients with bladder cancer. While the FGFR tyrosine kinase inhibitor erdafitinib has been approved as a targeted therapy for patients with FGFR3-altered (aFGFR3) bladder cancer, the response rate remains suboptimal, prompting development of strategies to improve treatment response. Here, we observed an immune-desert tumor microenvironment (TME) phenotype in human aFGFR3 bladder cancer and demonstrated that mutant FGFR3 indirectly induces a "cold" TME in mouse bladder cancer models. Single-cell RNA sequencing revealed the central role of macrophages in inducing the cold TME of aFGFR3 tumors. Macrophages in aFGFR3 tumors exhibited reduced T-cell recruitment and antigen presentation capabilities. Increased serine synthesis in bladder cancer cells that was induced by mutant FGFR3 activated the PI3K/Akt pathway in macrophages, shifting them to an immune-inert phenotype. Targeting PI3K in aFGFR3 tumors with duvelisib achieved promising efficacy by reversing the macrophage phenotype, and combination therapy with duvelisib and erdafitinib demonstrated increased antitumor activity. Overall, these findings reveal the critical role of enhanced serine synthesis efflux from cancer cells with mutant FGFR3 in shifting macrophages to an immune-inert phenotype. Reversing the macrophage phenotype holds promise for enhancing erdafitinib efficacy.SignificanceMetabolic reprogramming of bladder cancer cells driven by mutant FGFR3 increases serine synthesis that suppresses macrophage immunostimulatory functions to generate an immunosuppressive TME, which can be overcome by targeting PI3K.

| S-EPMC10722136 | biostudies-literature

Gene expression data from UMUC-14 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of UMUC-14 cell lines, which endogenously expressed a mutated activated form of FGFR3 (FGFR3-S249C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

2020-12-31 | GSE125547 | GEO

FGFR3 knock-down

Project description:FGFR3 knock-down

| PRJNA330963 | ENA

Gene expression data from MGH-U3 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of MGH-U3 cell lines, which were derived from a human bladder tumor and endogenously expressed a mutated activated form of FGFR3 (FGFR3-Y375C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

2018-02-16 | GSE84731 | GEO

Gene expression data from RT112 following FGFR3 knock-down using FGFR3 siRNAs

Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of RT112 cell lines, which were derived from a human bladder tumor and endogenously expressed the FGFR3-TACC3 fusion protein, the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.

2018-02-16 | GSE84732 | GEO

Profibrotic regulation of FGFR3 signaling in fibroblasts

Project description:We employed dermal fibroblasts isolated from Fgfr3G374Rneo+ mice, which do not express functional Fgfr3 (Fgfr3KO), from Fgfr3G374Rneo- mice with ligand-independent constitutive activation of Fgfr3 (Fgfr3Act) and from wildtype (WT) mice with normal expression of Fgfr3. Total RNA from these murine dermal fibroblasts (passage 4) were extracted and after quality control, were hybridized to the murine genome U74 gene chip. We have identified that Fgfr3 regulates important profibrotic pathways in fibroblasts. Selective upregulation of fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 promote fibroblast activation and tissue fibrosis Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 synergistically induces multiple profibrotic pathways including Endothelin-, Interleukin-4- and CTGF-signaling in a CREB-dependent manner. Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 inhibited fibroblast activation and attenuated experimental skin fibrosis. We have characterized FGFR3 as an upstream regulator of a network of profibrotic mediators and as a potential target for the treatment of fibrosis.

2020-10-01 | GSE148643 | GEO

Microarray of Human astrocytes transduced with lentivirus expressing FGFR3-TACC3 treated with vehicle, FGFR3-TACC3 treated with the FGFR inhibitor PD173074 for 12h, FGFR3-TACC3-K508M treated with vehicle or empty vector treated with vehicle

Project description:In order to interrogate the transcriptional changes elicited by FGFR3-TACC3, we expressed the FGFR3-TACC3 fusion protein in human astrocytes and compared the global gene expression profiles of cells treated with a specific inhibitor of FGFR3-TK (PD173074) or vehicle. FGFR3-TACC3 expressing HA were also compared with HA that expressed the kinase-inactive FGFR3-TACC3 (FGFR3-TACC3-K508M) and HA transduced with the empty vector. Gene Ontology-guided enrichment map demonstrated that, besides the expected enrichment for mitotic activity, oxidative phosphorylation and mitochondrial biogenesis were the most significant biological functions enriched in HA expressing active FGFR3-TACC3.

2017-10-17 | E-MTAB-6037 | 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

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

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