Search Results (287)

Hair follicle stem cells (HFSCs) are resident stem cells within hair follicles (HFs) that possess self-renewal and differentiation capacities, serving as a critical model for regenerative medicine research. Their dynamic interaction with dermal papilla cells (DPCs) plays a decisive role in HF development and cycling. FGF22 is a paracrine fibroblast growth factor that can regulate the proliferation, differentiation and migration of epithelial cells. This study established a DPC-HFSC co-culture system, revealing that FGF22 overexpression in DPCs significantly upregulated FGFR1/FGFR2 mRNA expression levels in HFSCs (p < 0.05), with a 1.67-fold increase in EdU-positive cell proportion (p < 0.01). CCK-8 assays demonstrated markedly enhanced HFSC viability (p < 0.01), with a 17% reduction in HFSC apoptosis (p < 0.05). Conversely, FGF22 knockout downregulated FGFR1/FGFR2 expression (p < 0.05), reduced HFSC proliferation capacity by 25% (p < 0.01), and increased HFSC apoptosis levels by 1.81-fold (p < 0.05). In addition, FGF22 overexpression promotes the proliferation and differentiation of HFSCs by activating Wnt/β-Catenin, Sonic Hedgehog (Shh) and Notch signaling pathways, or inhibiting BMP signaling pathways. Knockout of FGF22 weakens these processes and inhibits the activation and differentiation of HFSCs. This study, through the DPCs-HFSCs co-culture system, revealed the regulatory mechanism of FGF22 secreted by DPCs on the proliferation and differentiation of HFSCs, thereby providing theoretical references for fields such as fine-wool sheep breeding, human regenerative medicine, and hair loss treatment. Full article

Tooth agenesis (TA), the congenital absence of one or more teeth, is the most common manifestation of defective dental morphogenesis in humans. TA can occur as an isolated (non-syndromic) condition or as part of a broader syndromic presentation. In this review, we analyzed a total of 73 manuscripts to provide a comprehensive update on the genetic landscape of TA. To investigate the genes, variants, and associated phenotypes, we reviewed data from curated databases including Human Phenotype Ontology (HPO), OMIM, ClinVar and MalaCards. Based on the current evidence, the genes most frequently implicated in TA are MSX1, EDA, and PAX9. However, chromosomal abnormalities, such as those seen in Down syndrome and Williams syndrome, along with structural variations (e.g., deletions and duplications), also contribute significantly to TA etiology. The most involved pathways include TNF receptor binding, encompassing genes such as EDA, EDA2R, EDAR, and EDARADD, and the mTOR signaling pathway, which includes AXIN2, FGFR1, LRP6, WNT10A, and WNT10B. The aim of this review is to provide an critical synthesis of the genetic mechanisms underlying TA, highlighting the contribution of major signaling pathways, regulatory networks, and emerging molecular insights that may inform diagnostic and therapeutic advances. Full article

Bats are natural reservoirs for diverse viruses, yet they rarely develop disease, suggesting unique antiviral adaptations. In this study, we performed a comprehensive genome-wide analysis in the common vampire bat (Desmodus rotundus), integrating comparative genomics, functional annotation, microRNA (miRNA) discovery, target prediction, and network-based analyses. Comparative genomic analysis revealed that Phyllostomus discolor exhibits the highest protein homology (97.4%) with D. rotundus. Alignment of interferon regulatory factors (IRFs) indicated strong conservation of IRF1, IRF5, and IRF8, while IRF4 and IRF7 showed divergence, reflecting bat-specific modulation of interferon signaling. Functional annotation of previously uncharacterized proteins identified immune-related elements, including toll-like receptor 4, syncytin-1, and endogenous retroviral sequences, highlighting the integration of viral components into host immunity. We further identified 19 novel miRNAs in D. rotundus, with high-confidence target genes such as SOD2, TRIM28, and FGFR1 involved in antiviral defense, apoptosis regulation, and oxidative stress response. Functional enrichment analyses revealed processes associated with wound healing, apoptosis suppression, infection response, and longevity. Network entropy analysis highlighted central regulatory hubs, including MYC, BCL2, and KIF1B, influencing cell cycle, survival, and immune balance. Collectively, these results demonstrate that D. rotundus employs an integrated regulatory network combining conserved immune factors, lineage-specific gene divergence, and miRNA-mediated fine-tuning to achieve viral tolerance without pathology. This study expands our understanding of bat antiviral biology and provides candidate molecular targets for future functional and translational research. Full article

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody–drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. Methods: We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. Results: ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Conclusions: Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care. Full article

Resistance to conventional anti-tumor drugs is one of the significant challenges in oncology, responsible for treatment failure and patient death. Introduction of the targeted drugs (e.g., small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies) in cancer therapy significantly improved overall survival (OS) and progression-free survival (PFS) rates for selected groups of cancer patients and delayed the progression of advanced forms of human malignancies. However, the development of secondary resistance to the targeted drugs remains an unbeatable obstacle to a successful outcome in the long run, thereby making prognosis unfavorable for cancer patients with advanced, recurrent, and metastatic forms of disease. The review focuses on several mechanisms that regulate cancer resistance to conventional chemotherapies. This includes the upregulation of main types of ABC transporters (e.g., ABCB1, ABCC1, and ABCG2), which provides the efflux of chemotherapeutic agents from cancer cells. Additionally, the activation of diverse DNA damage repair (DDR) pathways, epithelial-to-mesenchymal transition (EMT), and the population of cancer stem cells (CSCs) are also discussed in detail, thereby illustrating the diverse molecular mechanisms of cancer sensitivity to chemotherapies. Recently, several TKIs, including those that were initially developed to specifically target FGFR and VEGFR pathways, have also been reported to exhibit “off-target” effects by interacting with ABC transporters and inhibiting their function. This, in turn, illustrates their potency in retaining chemotherapeutic agents within cancer cells and possessing a chemosensitizing function. Of note, FGFR and VEGFR inhibitors may behave as inhibitors or substrates of ABC transporters, depending on the expression of specific pumps and affinity for them, concentrations, and types of co-administered agents, thereby disclosing the complexity of this scenario. Additionally, the aforementioned RTKI can interfere with the other molecular mechanisms regulating tumor sensitivity to conventional chemotherapies, including the regulation of diverse DDR pathways, EMT, and the population of CSCs. Thereby, the aforementioned “off-target” functions of FGFR and VEGFR inhibitors can open novel approaches towards anti-cancer therapies and strategies aimed at counteracting cancer multidrug resistance (MDR), which is important especially as second- or third-line treatments in patients who have progressed on modern chemotherapeutic regimens. Notably, the strategy of using TKIs to potentiate the clinical efficacy of chemotherapies can extend beyond inhibitors of FGFR and VEGFR signaling pathways, thereby providing a rationale for repurposing existing TKIs as an attractive therapeutic approach to overcome cancer chemoresistance. Full article

Hepatocellular carcinoma (HCC) is a deadly liver cancer characterized by dysregulated signaling and aberrant cell-cycle control. The FGFR4/FGF19 pathway is dysregulated in HCC and other cancers. Inhibitors targeting the FGF19/FGFR4 pathway, including the FGF19/FGFR4 inhibitor FGF401, have been investigated in HCC and other cancers; however, nearly all patients who initially respond eventually develop resistance shortly after starting therapy, highlighting the urgent need for new treatment strategies to overcome drug resistance. In the present study, we report that chronic treatment of the FGF19/FGFR4-expressing HCC25−0705A line with FGF401 led to acquired resistance. FGF401-resistant tumors exhibited upregulation of FGFRs and activation of the PI3K/AKT/mTOR/p70S6K pathway. Combination therapy with FGF401 and the mammalian target of rapamycin (mTOR) inhibitor everolimus (FGF401/everolimus) resulted in more complete tumor growth inhibition, delayed the onset of resistance, and prolonged overall survival (OS) in mice bearing orthotopic HCC tumors. The FGF401/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19/FGFR4/mTOR-dependent tumors. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Background and Aim: DNA methylation may contribute to a worsening in breast cancer (BC). Methods: We conducted a matched case–control study to investigate the contribution of DNA methylation (DNAm) in breast cancer recurrence risk. Genome-wide DNAm profiles were generated from peripheral white blood cells (WBC) collected post-surgery from women with primary breast cancer BRCA wild-type, using Illumina Infinium HumanMethylationEPIC array. Cases had to experience recurrence of breast cancer or death and were matched to controls (subjects without recurrence, ratio 1:2) by age at diagnosis (+/− 5 years) and follow-up duration. Results: We identified three differentially methylated regions between the groups. Cases showed two hypomethylated regions, one upstream of the vtRNA2–1 gene (estimate −0.30, p-value < 0.005), and one in the 5′ UTR region of the FGFR2 gene (estimate −0.34, p-value < 0.028), whereas one, upstream of the RUFY1 gene (estimate 0.32, p-value < 0.015), was hypermethylated. Additionally, we identified two methylation signals, recognised as predictors of biochemical traits. The chemokine ligand 21 (unadjusted p-value < 0.03) and insulin receptor expression (unadjusted p-value < 0.04) were higher in cases than in controls. Conclusions: Our exploratory study suggests that specific DNA methylation patterns in WBCs, particularly in genes related to cellular proliferation, invasion, and glucose homeostasis, may be associated with the risk of breast cancer recurrence in BRCA wild-type women. If validated in larger cohorts, these circulating signatures may serve as blood-based biomarkers to improve risk stratification and guide tailored treatment strategies. Full article

Glioblastoma (GBM) is an aggressive and highly heterogeneous tumor that frequently recurs despite surgery followed by radio-chemotherapy and, more recently, TTFields. This recurrence is largely driven by glioblastoma stem cells (GSCs), which are intrinsically resistant to standard therapies. Identifying molecular targets that underlie this resistance is therefore critical. Here, we investigated whether the inhibition of FGFR1, previously identified as a key mediator of GBM radioresistance, using pemigatinib, a selective FGFR1–3 inhibitor, could enhance GSC radiosensitivity in vitro and in vivo. Pemigatinib treatment inhibited FGFR1 signaling, promoted proteasome-dependent FGFR1 degradation, and reduced the viability, neurosphere formation, and sphere size in GSCs with unmethylated MGMT, a subgroup known for poor response to standard treatments. In MGMT-unmethylated differentiated GBM cell lines, pemigatinib combined with temozolomide further enhanced radiosensitivity. Transcriptomic analysis revealed that pemigatinib treatment led to the downregulation of S100A4, a biomarker associated with mesenchymal transition, angiogenesis, and immune modulation in GBM. Functional studies confirmed that silencing S100A4 significantly improved GSCs’ response to irradiation. In vivo, pemigatinib combined with localized irradiation produced the longest median survival compared to either treatment alone in mice bearing orthotopic GSC-derived tumors, although the difference was not statistically significant. These findings support further clinical investigation to validate these preclinical findings and determine the potential role of FGFR inhibition as part of multimodal GBM therapy. Full article

We previously demonstrated that the activation of FGFR signaling in GIST may be a mechanism of GIST resistance to imatinib mesylate (IM). We show here that IM-resistant GIST cells lacking secondary KIT mutations overexpress claudin-1 on both transcriptional and translational levels. In contrast, a knockdown of CLDN1 or inhibition of its activity by PDS-0330 effectively restored GIST’s sensitivity to IM both in vitro and in vivo. This was evidenced by the increased expression of apoptotic markers (e.g., cleaved PARP and caspase-3) and the decreased proliferation rate of IM-resistant GIST T-1R cells treated with a combination of IM and PDS-0330 (or siRNA CLDN1). In concordance with these findings, a significant synergy was observed between IM and PDS-0330 in GIST T-1R cells. Importantly, decreased tumor size and weight were observed in IM-resistant GIST xenografts treated with a combination of IM and PDS-0330. Furthermore, the combined treatment of IM-resistant tumors induced an increase in intratumoral apoptosis and other changes, as defined by the histopathologic response rate. Based on the co-immunoprecipitation and immunofluorescence microscopy data, we also demonstrated the strong interaction pattern between CLDN1 and FGFR2. Of note, the inhibition or knockdown of CLDN1 effectively decreased the phosphorylation of FGFR2 and FRS-2, a well-known FGFR adaptor protein, thereby illustrating CLDN1’s ability to regulate FGFR-signaling and thereby promote FGFR-mediated survival in KIT-inhibited GIST. Consequently, CLDN1 inhibition in GIST effectively disrupted the FGFR-mediated pathway and re-sensitized tumor cells to IM. In concordance with these data, molecular profiling of CLDN1-inhibited GIST T-1R cells illustrated a significant decrease in the majority of FGFR transcripts, including FGFR2, 3, and 4. Additionally, several FGFR ligands (e.g., FGF14, -19, and -23) were also down-regulated in PDS-0330-treated GIST. Notably, exogenous FGF-2 increased CLDN1 expression in a time-dependent manner. In contrast, pan-FGFR inhibitors effectively reduced CLDN1 levels in IM-resistant GIST T-1R cells, thereby illustrating a cross-talk between CLDN1- and FGFR-mediated pathways in IM-resistant GIST. Based on subcellular fractionation and immunofluorescence microscopy data, we also observed partial relocalization of CLDN1 into the cytoplasm in IM-resistant GIST. Notably, PDS-0330 effectively abrogated this relocalization, suggesting that changes in CLDN1 subcellular distribution might also impact GIST resistance to IM. Lastly, based on our small cohort clinical study (n = 24), we observed the increased expression of CLDN1 in most “high-risk” primary GIST known to be associated with poor prognosis and aggressive behavior, thereby illustrating the prognostic value of increased CLDN1 expression in GIST and providing a further rationale to evaluate the effectiveness of CLDN1 inhibition for GIST therapy. Full article

Fibroblast growth factors (FGFs) play a key role in lung development by mediating complex interactions between epithelial and mesenchymal cells, which are central to processes such as branching morphogenesis, epithelial differentiation, and alveolarization. The findings regarding this interplay highlight the complexity of FGF signaling, as different FGFs contribute to various aspects of lung formation and maturation. Understanding the role of FGF proteins in shaping the lung is crucial for gaining insight into the biology of its development. Furthermore, FGFs orchestrate complex signaling pathways that regulate lung regeneration in adulthood. Therapeutic strategies targeting FGF-dependent pathways appear promising for repairing and improving lung function in diverse pulmonary diseases. In this review, we describe the current perception of the role of FGF proteins in lung development and regeneration, together with an overview of emerging therapeutic strategies aiming at FGF signaling in lung-related disorders. Full article

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

The thalamus is an important sensory relay station. It integrates all somatic sensory pathways (excluding olfaction) and transmits information through thalamic relay neurons before projecting to the cerebral cortex via thalamocortical axons (TCAs). Emerging evidence has shown that FGF3, a member of the morphogen family, is an axon guidance molecule that repels TCAs away from the hypothalamus and into the internal capsule so that they subsequently reach different regions of the cortex. However, current studies on FGF-mediated axon guidance predominantly focus on phenomenological observations, with limited exploration of the underlying molecular mechanisms. To address this gap, we investigated both direct and indirect downstream signaling pathways mediating FGF3-dependent chemorepulsion of TCAs at later developmental stages. Firstly, we used pharmacological inhibitors to identify the signaling cascade(s) responsible for FGF3-triggered direct chemorepulsion of TCAs, in vitro and in vivo. Our results demonstrate that the PC-PLC pathway is required for FGF3 to directly stimulate the asymmetrical repellent growth of developing TCAs. Then, we found the FGF3-mediated repulsion can be indirectly induced by Slit1 because the addition of FGF3 in the culture media induced an increase in Slit1 expression in the diencephalon. Furthermore, by using downstream inhibitors, we found that the indirect repulsive effect of FGF3 is mediated through the PI3K downstream pathway of FGFR1. Full article

The Sprouty (Spry) proteins modulate signalling and regulate processes like cellular migration and proliferation. Here, we investigated a Spry4 alteration substituting a lysine at position 177 to an arginine, based on a mutation found in Kallmann syndrome, a genetically heterogeneous disease connected to reduced fibroblast growth factor receptor1 (FGFR) signalling. Using growth curves to evaluate proliferative and scratch assays to determine migrative capacities of the cells, in normal fibroblasts as well as in osteosarcoma-derived cells, we demonstrate that the modified Spry4^K177R version hinders both processes, which the unaltered protein cannot do under the same conditions. The inhibition of these processes was accompanied by lower relative phospho-extracellular-signal-regulated kinases (pERK) levels in response to serum induction, indicating that activation of MAPK was less efficient. In contrast to the situation in these cells of mesenchymal origin, in lung cancer-derived cell lines both variants of Spry4 were able to interfere with proliferation of tested cells, and in the cells with elevated FGFR1 expression the Spry4 proteins with an alteration at codon 177 were even more effective. In summary, these data indicate that the lysine at position 177 restricts the ability of Spry4 to inhibit signal transduction at least in cells with high FGFR1 levels. Full article

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors with different clinical and biological characteristics. Ki-67 staining and mitotic counts are the most commonly used prognostic markers, but these methods are time-consuming and lack reproducibility, highlighting the need for innovative approaches that improve histological evaluation and prognosis. In our previous study, we observed that the microRNA (miRNA) expression profile of GEP-NENs correlates with the three grades of GEP-NENs. This study aimed to characterize a group of miRNAs that discriminate well-differentiated GEP-NENs grading 1 (G1) and grading (G2). Fifty formalin-fixed and paraffin-embedded tissue specimens from well-differentiated GEP-NENs G1 and G2 tissues were used for this study. The expression levels of 21 miRNAs were examined using qRT-PCR, while FGFR2 and FGF1 protein expression were evaluated through immunohistochemistry (IHC). We identified four miRNAs (hsa-miR-133, hsa-miR-150-5p, hsa-miR-143-3p and hsa-miR-378a-3p) that are downregulated in G2 GEP-NENs compared to G1. Bioinformatic analysis revealed that these miRNAs play a key role in modulating the FGF/FGFR signaling pathway. Consistent with this observation, we found that fibroblast growth factor receptor 2 (FGFR2) expression is markedly higher in G2 NENs patients, whereas its expression remains low in G1 NENs. Our findings highlight the potential use of miRNAs to confirm the histological evaluation of GEP-NENs by employing them as biomarkers for improving histological evaluation and tumor classification. Full article