Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in their target specificity as they generally inhibit all FGFRs and other receptor tyrosine kinases. In the search for specific inhibitors of human FGFR1, we identified VZ23, a DNA aptamer that binds to FGFR1b and FGFR1c with a KD of 55 nM and 162 nM, respectively, but not to the other FGFR variants (FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4). In cells, VZ23 inhibited the activation of downstream FGFR1 signaling and FGFR1-mediated regulation of cellular senescence, proliferation, and extracellular matrix homeostasis. Consistent with the specificity toward FGFR1 observed in vitro, VZ23 did not inhibit FGFR2-4 signaling in cells. We show that the VZ23 inhibits FGFR1 signaling in the presence of cognate fibroblast growth factor (FGF) ligands and its inhibitory activity is linked to its capacity to form unusual G-quadruplex structure. Our data suggest that targeting FGFR1 with DNA aptamers could be an effective alternative to TKIs for treating impaired FGFR1 signaling in human craniosynostoses.

• Publication type
• Journal Article MeSH

Rosette-forming glioneuronal tumors (RGNTs) with FGFR1 tyrosine kinase domain internal tandem duplication (FGFR1 ITD) is exceedingly rare, with only a few cases reported in the literature. Hereby we present a case of a tumor with RGNT morphology occurring in area of septum pellucidum of 43-year-old male. The tumor showed FGFR1 ITD, no PIK3CA, PIK3R1 or NF1 alterations and inconclusive methylation profile with match for class of "low-grade glial/glioneuronal/neuroepithelial tumors". No areas characteristic of dysembryoplastic neuroepithelial tumor were identified. A brief review of literature on discrepancies between morphological diagnosis of RGNT and molecular profile of the entity is provided.

• MeSH
• Adult MeSH
• Humans MeSH
• Brain Neoplasms * pathology   genetics   MeSH
• Neoplasms, Neuroepithelial * pathology   genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 1 * genetics   MeSH
• Tandem Repeat Sequences MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

• MeSH
• Squamous Cell Carcinoma of Head and Neck virology   pathology   genetics   MeSH
• Adult MeSH
• Phenotype MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Papillomavirus Infections * pathology   complications   genetics   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Head and Neck Neoplasms * pathology   virology   genetics   MeSH
• Microtubule-Associated Proteins genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 3 * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carcinoma, Squamous Cell pathology   genetics   virology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues. In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor. Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.

• MeSH
• Cilia * metabolism   genetics   MeSH
• Epithelial Cells * metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Receptor, Fibroblast Growth Factor, Type 1 metabolism   genetics   MeSH
• Receptor, Fibroblast Growth Factor, Type 2 * metabolism   genetics   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

• MeSH
• Fibroblast Growth Factor 10 * metabolism   genetics   chemistry   MeSH
• Humans MeSH
• Mice MeSH
• Lung metabolism   embryology   MeSH
• Receptors, Fibroblast Growth Factor metabolism   MeSH
• Signal Transduction * MeSH
• Protein Stability MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Development of dentition is a commonly studied process as a representative of the development of ectodermal derivates. A key step is the formation of a signaling center called the enamel knot (EK), which organizes tooth crown formation. In the mouse lower jaw, the anterior part of the tooth-forming region undergoes a series of complex events before the first molar primary EK can form more posteriorly and the tooth can progress through the cap stage. Although much is known about the molecular factors involved in tooth development, disentangling their specific roles is difficult. In this study, we circumvented this problem by isolating the posterior part of the tooth-forming region at embryonic day 13.5 and cultivating it in vitro. By treating them with molecules activating or inhibiting Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) pathways, we demonstrate that Shh plays the role of an inhibitor of EK formation, and we suggest that the FGF pathways may have both positive and negative roles, as seen in hair. By RNA-sequencing of the cultivated isolates after 0, 16, or 24 h in vitro, respectively, we screened for genes whose expression varies with EK and cap formation and pointed to Cdkn2b and Sema3b as 2 promising candidates in this process.

• MeSH
• Fibroblast Growth Factors physiology   MeSH
• Molar embryology   MeSH
• Mice MeSH
• Odontogenesis * physiology   genetics   MeSH
• Hedgehog Proteins physiology   metabolism   MeSH
• Signal Transduction MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Crown * embryology   MeSH
• Dental Enamel * embryology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND & AIMS: Exogenous recombinant fibroblast growth factor 20 (FGF20) protein has been proved to treat ulcerative colitis; however, its mechanism of action remains unclear. This study aimed to explore the role and mechanism of action of FGF20 in ulcerative colitis. METHODS: Data from patients with ulcerative colitis were analyzed using the Gene Expression Omnibus dataset. A murine colitis model was established by administering 2% dextran sodium sulfate. FGF20 knockout mice and Adenoassociated viruses (AAV)-FGF20-treated mice were used to elucidate the specific mechanisms. Proteomic analysis was conducted to identify differentially expressed genes. RESULTS: FGF20 levels were significantly elevated in the colonic tissues of subjects and mice with colitis. FGF20 deficiency exacerbated dextran sodium sulfate-induced colitis; in contrast, FGF20 replenishment alleviated colitis through 2 principal mechanisms: restoration of impaired intestinal epithelial barrier integrity, and inhibition of M1 macrophage polarization. Notably, S100A9 was identified as a pivotal downstream target of FGF20, which was further demonstrated by pharmacologic inhibition and overexpression experiments of S100A9 using paquinimod (a specific inhibitor of S100A9) and AAV-S100A9 in FGF20 knockout and AAV-FGF20 mice with colitis, respectively. Additionally, the nuclear factor-κB pathway was found to be involved in the process by which FGF20 regulates S100A9 to counteract colitis. CONCLUSIONS: These results suggest that FGF20 acts as a negative regulator of S100A9 and nuclear factor-κB, thereby inhibiting M1 macrophage polarization and restoring intestinal epithelial barrier integrity in mice with dextran sodium sulfate-induced colitis. FGF20 may serve as a potential therapeutic target for the treatment of ulcerative colitis.

• MeSH
• Fibroblast Growth Factors * metabolism   genetics   pharmacology   MeSH
• Calgranulin B * metabolism   genetics   MeSH
• Colitis * chemically induced   MeSH
• Humans MeSH
• Macrophages * immunology   metabolism   drug effects   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• NF-kappa B * metabolism   MeSH
• Signal Transduction MeSH
• Dextran Sulfate toxicity   MeSH
• Intestinal Mucosa * pathology   metabolism   immunology   drug effects   MeSH
• Colitis, Ulcerative * pathology   chemically induced   immunology   metabolism   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The neuropeptide B/W signalling system (NPB/W) has been identified in multiple body regions and is integral to several physiological processes, including the regulation of food intake and energy homeostasis. Recently, it has also been detected in human skin; however, its specific functions in this context remain to be thoroughly investigated. This study aims to identify the expression of neuropeptides B/W receptor 1 (NPBWR1) and neuropeptides B/W receptor 2 (NPBWR2) in human dermal fibroblasts of mesenchymal origin using genomic and proteomic techniques. We will also investigate the role of these receptors in cell proliferation and calcium signalling. METHODS: The mRNAs for NPBWR1 and NPBWR2 were detected using quantitative PCR (qPCR) analysis and further validated by western blot and immunofluorescence analyses. Additionally, we synthesised ligands for these receptors, specifically hNPB (25-53) and hNPW (33-62), to investigate their effects on cell proliferation and intracellular calcium levels in human fibroblasts. RESULTS: Our results demonstrated that hNPW (33-62) has anti-proliferative effect on human dermal fibroblasts and concentration of 0.1-μmol/L can significantly decrease intracellular calcium levels (p < 0.05). CONCLUSION: This finding suggests a potential role for the NPB/W signalling system in pathologies associated with impaired calcium handling, such as fibrosis. Furthermore, we observed that the proliferation of human fibroblasts was not affected by hNPB (25-53). Our findings could lead to the development of new therapeutic strategies for various skin conditions and improved wound healing.

• MeSH
• Fibroblasts * metabolism   MeSH
• Cells, Cultured MeSH
• Skin * metabolism   cytology   MeSH
• Humans MeSH
• Neuropeptides metabolism   genetics   MeSH
• Cell Proliferation * MeSH
• Receptors, Neuropeptide metabolism   genetics   MeSH
• Signal Transduction MeSH
• Calcium * metabolism   MeSH
• Calcium Signaling MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21's protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.

• MeSH
• Adiponectin * metabolism   genetics   MeSH
• Diet, High-Fat * adverse effects   MeSH
• Energy Metabolism * drug effects   MeSH
• Fibroblast Growth Factors * metabolism   genetics   MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Myocytes, Cardiac * metabolism   drug effects   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase * metabolism   genetics   MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Signal Transduction MeSH
• Mitochondria, Heart * metabolism   drug effects   MeSH
• Heart Failure * metabolism   prevention & control   genetics   MeSH
• Stroke Volume drug effects   MeSH
• Adipose Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope 161Tb, for targeted therapy in FGFR-overexpressing cancer cells. FGF1 was engineered (eFGF1) to incorporate a single cysteine at the C terminus for site-specific labeling with a DOTA chelator. eFGF1-DOTA was mixed with the radioisotope 161Tb under mild conditions, resulting in a labeling efficiency above 90%. The nonradioactive ligands were characterized by mass spectrometry, while radioligands were characterized by thin-layer chromatography. The targeting function of the radioligands was assessed through confocal microscopy, flow cytometry, and Western blot analysis, focusing on binding to cancer cells and the activation of downstream signaling pathways related to FGFR. When compared to MCF-7 and RD cell lines with low FGFR expression, eFGF1-DOTA-Tb[161Tb] radioligands demonstrated significantly higher accumulation in FGFR-overexpressing cell lines (MCF-7 FGFR1 and RMS559), leading to enhanced cytotoxicity. Besides radionuclides, eFGF1 can also deliver doxorubicin (DOX) into cancer cells. Considering these characteristics, eFGF1-DOTA-Tb[161Tb] and eFGF1-DOX emerge as promising candidates for FGFR-targeted cancer therapy, and further evaluation in vivo is warranted.

• Publication type
• Journal Article MeSH