Related Experiment Video
Updated: Sep 13, 2025
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
FGFR1/3 Signaling as an Achilles' Heel of Phenotypic Diversity in Urothelial Carcinoma
Renate Pichler1, Nils C H van Creij2, Laura S Mertens3
1Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
Abstract:
FGFR inhibitors are a new therapeutic option for urothelial carcinoma (UC) with FGFR2/3 alterations. In this study, we analyzed genetic alterations, co-regulation, and differential expression for 45 genes encoding FGF, FGFR, or FGF-binding proteins (FGFBPs) in five published UC cohorts (n = 3939 MIBC) and 39 UC cell lines (DepMap portal). Network analyses identified FGFR1/3 genes as critical oncogenic hubs, co-regulated with their ligands and co-receptors, and abundantly expressed at protein level in the HPA immunohistochemistry data set. Machine learning with 38 FGFR-, FGF-, and FGFBP-coding transcripts reproduced consensus molecular subtypes with high accuracy of 0.72-0.84 (Cohen's κ 0.59-0.77). FGFR3 mutations in the transmembrane/hinge region, which were enriched in luminal papillary tumors, trigger ligand-independent signaling. Conversely, overexpression of FGFR1 and its ligands and accessory protein transcripts indicates ligand-dependent FGFR1 signaling in stroma-rich and basal/squamous subtypes. The sensitivity of most DepMap UC cell lines to pan-FGFR inhibitors in the GDSC and PRISM drug screens was independent of FGFR3 alterations. In vitro, erdafitinib reduced proliferation in FGFR wild-type UC cell lines in a similar manner to FGFR3-mutated cell lines. Our findings highlight FGFR1 and FGFR3 as pivotal signaling pathways with distinct, molecular subtype-specific activation mechanisms. The results suggest that FGFR inhibitors may have therapeutic applications beyond UC tumors with FGFR2/3 alterations.
Insights
Fibroblast Growth Factor Receptor (FGFR) inhibitors show promise for urothelial carcinoma (UC). This study reveals FGFR1 and FGFR3 pathways have distinct activation mechanisms, suggesting broader therapeutic potential beyond FGFR2/3 alterations in UC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibroblast Growth Factor Receptor (FGFR) inhibitors represent a novel therapeutic strategy for urothelial carcinoma (UC) harboring specific genetic alterations.
- Understanding the complex signaling networks involving FGF, FGFR, and FGF-binding proteins (FGFBPs) is crucial for optimizing treatment strategies.
Purpose of the Study:
- To analyze genetic alterations, co-regulation, and differential expression of 45 FGF, FGFR, and FGFBP-coding genes in urothelial carcinoma.
- To identify key oncogenic signaling hubs and their activation mechanisms across different molecular subtypes of UC.
- To investigate the potential of FGFR inhibitors in UC beyond tumors with known FGFR2/3 alterations.
Main Methods:
- Analysis of genetic alterations and gene expression in five published UC cohorts (n=3939) and 39 UC cell lines.
- Network analyses to identify co-regulated genes and critical oncogenic hubs.
- Machine learning models to classify molecular subtypes using transcript data.
- Evaluation of drug sensitivity in cell lines and in vitro proliferation assays.
Main Results:
- FGFR1 and FGFR3 were identified as critical oncogenic hubs, co-regulated with ligands and co-receptors, and expressed at the protein level.
- Machine learning accurately reproduced consensus molecular subtypes based on FGFR, FGF, and FGFBP transcripts.
- FGFR3 mutations activate ligand-independent signaling, while FGFR1 overexpression suggests ligand-dependent signaling in specific subtypes.
- FGFR inhibitor sensitivity in cell lines was largely independent of FGFR3 alterations, with erdafitinib showing efficacy in FGFR wild-type UC.
Conclusions:
- FGFR1 and FGFR3 signaling pathways are pivotal in UC, with distinct, subtype-specific activation mechanisms.
- FGFR inhibitors may offer therapeutic benefits for a broader range of UC patients, including those without FGFR2/3 alterations.
- These findings underscore the importance of characterizing FGFR pathway activation across diverse UC molecular subtypes.
More Related Videos
09:37Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
09:08Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Related Concept Videos
02:38Mitogens and the Cell Cycle
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
01:22Diversity in Cell Signaling Responses
Graded and Abrupt Responses
Some signaling systems generate...
01:17Intracellular Signaling Affects Focal Adhesions
Some...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:24Regulation of Angiogenesis and Blood Supply