Fibroblast Growth Factor Receptor Research Articles

FGFR2 in the Development and Progression of Cutaneous Squamous Cell Cancer.

Cutaneous squamous cell carcinoma (cSCC) is an increasingly common malignancy of the skin and the leading cause of death from skin cancer in adults over the age of 85. Fibroblast growth factor receptor 2 (FGFR2) has been identified as an important effector of signaling pathways that lead to the growth and development of cSCC. In recent years, there have been numerous studies evaluating the role FGFR2 plays in multiple cancers, its contribution to resistance to anticancer therapy, and new drugs that may be used to inhibit FGFR2. This review will provide an overview of our current understanding of FGFR2 and potential mechanisms in which we can target FGFR2 in cSCC. The goals of this review are the following: (1) to highlight our current knowledge of the role of FGFR2 in healthy skin and contrast this with its role in the development of cancer; (2) to further explain the specific molecular mechanisms that FGFR2 uses to promote tumorigenesis; (3) to describe how FGFR2 contributes to more invasive disease; (4) to describe its immunosuppressive effects in skin; and (5) to evaluate its effect on current anticancer therapy and discuss therapies on the horizon to target FGFR2 related malignancy.

Plain language summary: an analysis of the safety of futibatinib treatment in people with different types of cancer.

Researchers combined information from three separate phase 1 and 2 clinical trials, including over 400 people who had one of 33 different cancer types and who all received futibatinib in their clinical trial. This type of study is called a pooled analysis. Futibatinib is taken orally (by mouth) as a tablet and works by reducing the activity of a group of proteins called fibroblast growth factor receptors (FGFRs). FGFRs drive the growth of some cancers, especially cancer cells with changes in FGFR genes that make the proteins more active. Researchers wanted to look at how common some side effects were in people treated with futibatinib, how soon the side effects happened after taking futibatinib, and how they could be managed. Researchers also wanted to provide recommendations to other health care professionals on how to manage these side effects in people with cancer. In this analysis, the researchers focused on side effects that they had seen in previously completed trials of futibatinib. Overall, futibatinib was safe and tolerable. Most people (82%) had a high phosphate level in their blood (hyperphosphatemia), 27% had nail disorders, 27% had liver side effects (changes in liver-related laboratory tests), 19% had a sore mouth (stomatitis), 13% had hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome), 9% had a rash, 8% developed changes in the back of the eye (retinal disorders), and 4% of people developed cataracts. Most side effects were mild/moderate and reversible. The median time it took from starting treatment to experiencing a severe side effect ranged from 9days (hyperphosphatemia) to 125days (cataracts). Some side effects tended to occur early, while others developed later. Only 2% of people stopped taking futibatinib due to treatment-related side effects, and futibatinib caused no deaths. The side effects from taking futibatinib were manageable and similar in people with different types of cancer. To fully understand the safety of futibatinib, researchers will need to look at what side effects are reported in people taking futibatinib over a longer time in the real-world setting (outside of clinical trials).

Growth plate closure and therapeutic interventions.

Height gains result from longitudinal bone growth, which is largely dependent on chondrocyte differentiation and proliferation within the growth plates of long bones. The growth plate, that is, the epiphyseal plate, is divided into resting, proliferative, and hypertrophic zones according to chondrocyte characteristics. The differentiation poten-tial of progenitor cells in the resting zone, continuous capacity for chondrocyte differentiation and proliferation within the proliferative zone, timely replacement by osteocytes, and calcification in the hypertrophic zone are the 3 main factors controlling longitudinal bone growth. Upon ade quate longitudinal bone growth, growth plate senescence limits human body height. During growth plate senescence, progenitor cells within the resting zone are deplet ed, proliferative chondrocyte numbers de crease, and hypertrophic chondrocyte number and size decrease. After senescence, hypertrophic chondrocytes are replaced by osteocytes, the extracellular matrix is calcified and va-scularized, the growth plate is closed, and longitudinal bone growth is complete. To date, go nadotropin-releasing hormone analogs, aromatase inhi bitors, C-type natriuretic peptide analogs, and fibroblast growth factor receptor 3 inhibitors have been studied or used as therapeutic interv-entions to delay growth plate closure. Complex networks of cellular, genetic, paracrine, and endocrine signals are involved in growth plate closure. However, the detailed mechanisms of this process remain unclear. Further eluci-dation of these mechanisms will enable the development of new thera peutic modalities for the treatment of short stature, precocious puberty, and skeletal dysplasia.

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Supplementation of 3'-Sialyllactose During the Growth Period Improves Learning and Memory Development in Mice.

3'-Sialyllactose (3'-SL), a major acidic oligosaccharide found in human milk, has been investigated to improve cognitive-enhancing effects with 3 weeks old C57BL/6 mice by administering 3'-SL orally at a dose of 350 mg/kg/day for 6 weeks. Behavioral tests indicated that supplementation with 3'-SL promoted cognitive and memory development in young mice. Through interaction network and coenrichment analysis, nine differentially expressed genes (DEGs) related to memory and cognition were identified and localized in the hippocampal tissue of mice. The intervention of 3'-SL significantly increased the metabolism of sialic acid in mouse hippocampal tissue and promoted the expression of learning-related genes (p < 0.05). Notably, it increased the expression of genes associated with neural cell adhesion molecule (NCAM, p < 0.05), glutamate receptors, and fibroblast growth factor receptor (FGFR, p < 0.05). This suggests that 3'-SL may elevate polysialylated NCAM (PSA-NCAM) levels, which could subsequently interact with FGFR and glutamate receptors, thereby enhancing synaptic growth and plasticity. Additionally, 3'-SL altered the composition of the mouse intestinal microbiota. The synergistic action of gut microbiota and intestinal sialidase promoted the production of free sialic acid, providing essential nutritional elements for the development of the brain's nervous system. In conclusion, our findings provide new insights into the promoting effect of 3'-SL on cognitive development in growing mice and elucidate its molecular mechanisms.

Structural analysis of the stable form of fibroblast growth factor 2 – FGF2-STAB

Fibroblast growth factor 2 (FGF2) is a signaling protein that plays a significant role in tissue development and repair. FGF2 binds to fibroblast growth factor receptors (FGFRs) alongside its co-factor heparin, which protects FGF2 from degradation. The binding between FGF2 and FGFRs induces intracellular signaling pathways such as RAS-MAPK, PI3K-AKT, and STAT. FGF2 has strong potential for application in cell culturing, wound healing, and cosmetics but the potential is severely limited by its low protein stability. The thermostable variant FGF2-STAB was constructed by computer-assisted protein engineering to overcome the natural limitation of FGF2. Previously reported characterization of FGF2-STAB revealed an enhanced ability to induce MAP/ERK signaling while having a lower dependence on heparin when compared with FGF2-wt. Here we report the crystal structure of FGF2-STAB solved at 1.3 Å resolution. Protein stabilization is achieved by newly formed hydrophobic interactions, polar contacts, and one additional hydrogen bond. The overall structure of FGF2-STAB is similar to FGF2-wt and does not reveal information on the experimentally observed lower dependence on heparin. A noticeable difference in flexibility in the receptor binding region can explain the differences in signaling between FGF2-STAB and its wild-type counterpart. Our structural analysis provided molecular insights into the stabilization and unique biological properties of FGF2-STAB.

Cataracts Associated With Fibroblast Growth Factor Receptor Inhibitors for Cholangiocarcinoma

Since fibroblast growth factor receptor inhibitors (FGFRi) are used for treatment of intrahepatic cholangiocarcinoma (iCCA), understanding potential complications following longer-term use in clinical practice settings is warranted. This study describes cataract formation or progression as a complication of FGFRi use for the treatment of iCCA, even after treatment discontinuation. To describe cases of cataract formation or worsening in patients with iCCA treated with FGFRi and to characterize the ophthalmologic features, risk factors, and outcomes for FGFRi-associated cataracts. This retrospective case series study used data from patients with iCCA harboring FGFR2 aberrations who received FGFRi in clinical trials or as standard therapy from the University of California, San Francisco, Hepatobiliary Tissue Bank and Registry. Data were collected from patient visits between February 2015 and October 2021, and this retrospective investigation was conducted from September 6, 2022, to May 4, 2023. Data analysis was conducted from May 5, 2023, to September 6, 2023. Use of an FGFRi for the treatment of iCCA. The primary outcome was designated as development of a new or worsening cataract after FGFRi initiation. Statistical analysis for the association between cataract formation and clinical covariates was performed using unpaired t tests and Fisher exact tests. A single bivariate logistic regression model was used to examine total duration of FGFRi therapy and age at the conclusion of FGFRi therapy as predictors of cataract development. A total of 18 patients were included in the study; median (range) patient age was 54 (27-81) years, and 13 patients (72%) were female. Nine patients (50%) developed a cataract or had cataract progression in at least 1 eye after initiation of FGFRi. Of 17 eyes with cataract, 8 eyes (47%) required cataract surgery. One patient rapidly developed a cataract associated with phacomorphic glaucoma, which required urgent surgery. The median (range) time to cataract onset or worsening from initiation of FGFRi was approximately 18 (1-23) months. Five of 9 patients (56%) who developed cataracts or had cataract progression were diagnosed with new or worsening cataracts after discontinuation of FGFRi. Patients who developed cataracts had longer median (range) duration of FGFRi treatment compared with patients who did not develop cataracts (13 months [2-26] vs 5 months [1-11]; odds ratio, 1.01; 95% CI, 1.00-1.02; P = .02). While this retrospective case series study cannot prove cause and effect conclusively due to the study design, study results highlight cataract formation or progression as a potential adverse effect of FGFRi therapy, supporting consideration of periodic eye examinations in patients who have received this treatment.

Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice（2024 edition）

Neuroendocrine neoplasms are a group of heterogeneous tumors originating from the neuroendocrine system, which can occur in any part of the body. Pulmonary and gastroenteropancreatic neuroendocrine tumors are the most common. In recent years, the global incidence of neuroendocrine tumors has increased more significantly than other types of tumors, especially in the past 40 years. The drug treatment of neuroendocrine tumors includes somatostatin analogues, anti-angiogenesis targeting drugs, nuclide therapy and chemotherapy. Surufatinib is an oral tyrosine kinase receptor inhibitors that targets for vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor-1 receptor (CSF-1R), has received approval in 2020 and 2021 for the treatment of locally advanced or metastatic, progressive nonfunctional, well-differentiated (G1, G2) neuroendocrine tumors (NETs) of both pancreatic and extrapancreatic origin that are unresectable. Ongoing exploratory studies are investigating its potential application in other tumor types. Common adverse reactions observed during surufatinib treatment include hypertension, proteinuria, bleeding events, and hepatic lab test abnormal and diarrhea. Chinese multidisciplinary expert consensus on the rational use of surufatinib in clinical practice (2024 edition) aims to provide standardized guidance for its rational use and enhance patient compliance to maximize therapeutic benefits.

Characterization of Fibroblast Growth Factor Receptor Alterations and Activation in Patients with High-Risk Non-Muscle Invasive Bladder Cancer.

The GARNER study investigated fibroblast growth factor receptor (FGFR) alteration (ALT) frequency and the clinical outcome relationship with Bacillus Calmette-Guérin (BCG) treatment in high-risk non-muscle invasive bladder cancer (HR-NMIBC). An FGFR predictive response signature (FGFR-PRS) was discovered that identifies patients with an activated FGFR pathway who could potentially benefit from FGFR-targeted therapy beyond those who are FGFR ALT (+). Pre-treatment tumor samples and clinical data were analyzed from 582 BCG-treated HR-NMIBC patients. FGFR-PRS was discovered using a separate BC dataset and applied to the GARNER and other BC cohorts. FGFR-PRS was also applied to in vitro data from UC cell lines treated with FGFR-active agents. 31% of pre-treatment GARNER HR-NMIBC tumors were FGFR ALT (+) but this was not significantly associated with BCG response. For the subset of patients with paired pre- and post-BCG treatment samples, nearly one-third pre-treatment ALT (+) patients were ALT (-) post-treatment. FGFR-PRS identified patients with an activated FGFR pathway and identified approximately 2-fold additional patients compared to ALT status alone, and this increase was similar across tumor stage. A positive relationship between tumor growth inhibition and FGFR-PRS score was shown in BC in vitro models treated with FGFR-active agents. These data provide support for FGFR-targeted therapy use in FGFR ALT (+) HR-NMIBC and describe tumors with shared FGFR pathway-activated biology that are FGFR ALT (-) but FGFR-PRS (+). The latter suggests a broader potential patient population for FGFR-targeted therapy, which will require subsequent validation in patients treated with FGFR-targeted therapy.

Bihemispheric IDH-Wildtype Glioblastoma with Unilateral FGFR3-TACC3 Fusion in Patient with Breast Cancer History: A Case Report and Literature Review

Abstract Introduction/Objective Adult IDH-wild type glioblastomas comprise a heterogeneous spectrum of neoplasms, characterized by poor prognosis and resistance to the chemoradiotherapy. For WHO integrated diagnosis classification and to establish treatment options, molecular analysis is necessary. Herein, we present a case of a glioblastoma, IDH-wildtype with involvement of both cerebral hemispheres and an uncharacteristic in-frame fusion limited to one hemisphere. Methods/Case Report The patient is a 52-year-old woman with past medical history of metastatic breast cancer who presented with headache and worsening facial pain. Brain magnetic resonance imaging brain demonstrated a right frontal lobe lesion with vasogenic edema. The patient was treated with Gamma Knife radiosurgery. Scans revealed enlargement and a new left frontal lobe lesion. Bihemispheric tumor resection and GammaTile placement was undertaken. Results (if a Case Study enter NA) Histologically, the tumor was composed of hypercellular astrocytes, microvascular proliferation, and necrosis with no evidence of metastatic disease. Immunohistochemistically, neoplastic cells showed glial fibrillary acidic protein expression and elevated Ki-67 proliferation index. Molecular examination revealed in the right hemisphere lesion post-radiation (1) FGFR3::TACC3 (exon 17::exon 11) fusion and (2) TERT promoter, while the left hemisphere lesion which did not receive radiation showed clinically relevant variants in (1) TERT promoter, (2) TP53, (3) NF1, and (3) PIK3CA without identification of a fusion. An integrated diagnosis of glioblastoma, IDH- wildtype, CNS WHO grade 4 was established bilaterally. Conclusion The fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil 3 (TACC3) fusion is identified as a rare molecular feature in glioblastomas with an estimated prevalence of 4%. Clinical trials suggest that F3T3-positive tumors have a better prognosis than those without the translocation. The identification of the oncogenic FGFR3-TACC3 fusion highlights the possibility of identifying patients potentially responsive to targeted therapy with FGFR kinase inhibitors. The significance of the molecular differences in the right and left hemisphere lesions is uncertain; glioblastomas are heterogeneous tumors with intra-and intertumoral heterogeneity but it may suggest independent origins.

Advances in the role of membrane-bound transcription factors in carcinogenesis and therapy.

Protein shuttling between the cytoplasm and nucleus is a unique phenomenon in eukaryotic organisms, integral to various cellular functions. Membrane-bound transcription factors (MTFs), a specialized class of nucleocytoplasmic shuttling proteins, are anchored to the cell membrane and enter the nucleus upon ligand binding to exert their transcriptional regulatory functions. MTFs are crucial in cellular signal transduction, and aberrant nucleocytoplasmic shuttling of MTFs is closely associated with tumor initiation, progression, and resistance to anticancer therapies. Studies have demonstrated that MTFs, such as human epidermal growth factor receptor (HER), fibroblast growth factor receptor (FGFR), β-catenin, Notch, insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor (IR), play critical roles in tumorigenesis and cancer progression. Targeted therapies developed against HERs and FGFRs, among these MTFs, have yielded significant success in cancer treatment. However, the development of drug resistance remains a major challenge. As research on MTFs progress, it is anticipated that additional MTF-targeted therapies will be developed to enhance cancer treatment. In this review, we summarized recent advancements in the study of MTFs and their roles in carcinogenesis and therapy, aiming to provide valuable insights into the potential of targeting MTF pathways for the reseach of therapeutic strategies.

Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.

FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand. To determine whether FGF23/FGFR4 contributes to physiologic cardiac hypertrophy, we studied FGFR4 knockout mice (FGFR4-/-) during late pregnancy. In comparison to virgin littermates, pregnant wild-type and FGFR4-/- mice showed increases in serum FGF23 levels and heart weight; however, the elevation in myocyte area observed in pregnant wild-type mice was abrogated in pregnant FGFR4-/- mice. This outcome was supported by treatments of cultured cardiac myocytes with serum from fed Burmese pythons, another model of physiologic hypertrophy, where the co-treatment with an FGFR4-specific inhibitor abrogated the serum-induced increase in cell area. Interestingly, we found that in pregnant mice, the heart, and not the bone, shows elevated FGF23 expression, and that increases in serum FGF23 are not accompanied by changes in phosphate metabolism. Our study suggests that in physiologic cardiac hypertrophy, the heart produces FGF23 that contributes to hypertrophic growth of cardiac myocytes in a paracrine and FGFR4-dependent manner, and that the kidney does not respond to heart-derived FGF23.

Fibroblast Growth Factor Receptor 1-Specific Dehydrogelation to Release Its Inhibitor for Enhanced Lung Tumor Therapy.

Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (Nap-Y), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib (Nin) to form a peptide hydrogel Gel Y/Nin for localized administration and FGFR1-triggered release of Nin. Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Y in Gel Y/Nin is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H2PO3)-OH (Nap-Yp), leading to dehydrogelation of the gel and subsequent Nin release. In vitro experiments demonstrate that the release of Nin in a sustained manner from Gel Y/Nin significantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that Gel Y/Nin exhibits enhanced therapeutic efficacy on lung tumor than free Nin. We anticipate that Gel Y/Nin will be utilized for lung cancer treatment in clinical settings in the near future.

Determination of FGFR1 Functions in Cytarabine Treatment of Acute Myeloid Leukemia Through Bioinformatics Analysis

Aim: Among the most prevalent subtypes of acute leukemia is acute myeloid leukemia (LAML). Consequently, it is essential to understand the molecular causes of LAML and find its predictive and diagnostic biomarkers. The aim of this study is to determine the molecular functions of fibroblast growth factor receptor 1(FGFR1) involved in LAML pathogenesis and its potential therapeutic effect for AML treatment. Methods: The molecular docking interaction of the Cytarabine with its target FGFR1 was examined. The Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2), and UALCAN tools database were used to obtain the LAML gene expression datasets. Gene functional annotation was performed to investigate the DEGs' possible role. Using the Interactive Gene database retrieval tool (STRING) and a few chosen hub modules from the GeneMANIA database, the protein- protein interaction (PPI) network were constructed. A survival analysis was performed on the effects of hub genes on the overall survival of LAML patients. Results: As a result of docking, a strong interaction was observed between cytarabine and FGFR1. It has been discovered that cytarabine can reverse FGFR1 expression. The survival study results showed an association between the prognosis of AML patients and one of the central genes, FGFR1. Conclusion: The expression profile and functions of FGFR1 were determined in LAML patients. It has been shown that FGFR1 can be a viable therapeutic target for LAML and a possible biomarker for diagnosis.

Immune-mediated Neuropathy with Tri-sulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies in Pediatric Patients: A Case Series

Immune-mediated Neuropathy with Tri-sulfated Heparin Disaccharide or Fibroblast Growth Factor Receptor 3 Antibodies in Pediatric Patients: A Case Series

Clinicopathological characteristics and prognosis of combined hepatocellular cholangiocarcinoma

There is limited research on the clinicopathological characteristics of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) currently. The aim of this study is to summerize the clinicopathological factors and prognosis of cHCC-CCA, which could help us understand this disease. 72 cases of cHCC-CCA from West China Hospital of Sichuan University were collected. Tissue components were reviewed by pathologists. Immunohistochemistry was used to detect the status of mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) in cHCC-CCA, as well as the quantity and distribution of CD3+ T cells and CD8+ T cells. Fluorescence in situ hybridization was used to detect fibroblast growth factor receptor 2 (FGFR2) gene alteration. COX univariate and multivariate analyses were used to evaluate risk factors, and survival curves were plotted. 49 cases were classified as classic type cHCC-CCA and 23 cases as intermediate cell carcinoma. The cut-off value for diagnosing classic type was determined to be ≥ 30% for the cholangiocarcinoma component based on prognostic calculations. All tumors were MMR proficient. The rate of strong HER2 protein expression (3+) was 8.3%, and the frequency of FGFR2 gene alteration was 26.4%. CD3+ T cells and CD8+ T cells were mainly distributed at the tumor margin, and were protective factors for patients with cHCC-CCA. The overall survival of the 72 patients was 18.9 months, with a median survival of 12 months. Tumor size, TNM stage, and serum AFP level were prognostic factors for cHCC-CCA. The proportion of cholangiocarcinoma component reaching the threshold of 30%, may provide a reference for future pathology diagnosis. FGFR2 gene alteration was 26.4%, providing a clue for anti-FGFR2 therapy. However, more data is needed for further verification.

7434 Modulation of FGFR-FGF2-FGF23 Signaling Partially Rescues Osteoarthritis in Hyp Mice Homolog of Human X- Linked Hypophosphatemia

Abstract Disclosure: M.M. Hurley: None. L. Xiao: None. Human with X-linked hypophosphatemia (XLH) and its Hyp mice homolog develop several phenotypic abnormalities due to phosphate wasting mediated by abnormal Fibroblast Growth Factor Receptor-1 (FGFR1) and Fibroblast Growth Factor 23 (FGF23) signaling. XLH and Hyp mice also develop severe osteoarthropathy (OA) whose etiology is not fully defined. We previously reported that Fibroblast growth factor 2 (FGF2) regulates FGF23, specifically, mice overexpressing the high molecular weight FGF2 isoforms (HMWFGF2) in osteoprogenitors phenocopy Hyp mice including development of OA that worsens with age. Since we also reported that Hyp mice overexpress HMWFGF2 isoforms in osteoblasts and osteocytes, we examined whether the knee OA phenotype in Hyp mice was associated with aberrant FGFR1, FGF2, FGF23 signaling in knee joint articular cartilage and subchondral bone and whether in vivo FGFR tyrosine kinase inhibitor BGJ398 would modulate the OA phenotype in knee joints of Hyp mice. Ten weeks-old Control and Hyp mice were treated with Vehicle or BGJ398 for 12 weeks. Safranin-O staining of knee articular cartilage for proteoglycan revealed decreased staining in Hyp vehicle-treated mice that was partially restored to the cartilage thickness of Control mice in the Hyp-BGJ398-treated group. Significantly increased degradative enzyme matrix metalloproteinase-13 (MMP-13) in Hyp vehicle-treated knee articular cartilage was significantly reduced by BGJ398. Immunostaining revealed significantly increased phosphorylated FGFR1, FGF2 and FGF23 in both articular cartilage and subchondral bone. While BGJ398 significantly reduced immunostaining for phosphoFGFR1 and FGF2 in both articular cartilage and subchondral bone, it significantly reduced FGF23 in subchondral bone but not in articular cartilage. Significantly increased phospho-ERK1/2 labeling in Hyp-vehicle treated articular cartilage was partially rescued by BGJ398. This study demonstrates that increased FGFR1/FGF2 signaling contributes to OA in Hyp mice that can be partially rescued by FGF receptor inhibitor via reduction in MAPK signaling. Presentation: 6/1/2024

Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress.

Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.

New CRISPR/Cas9-based Fgfr2C361Y/+ mouse model of Crouzon syndrome exhibits skull and behavioral abnormalities.

Crouzon syndrome (CS), a syndromic craniosynostosis, is a craniofacial developmental deformity caused by mutations in fibroblast growth factor receptor 2 (FGFR2). Previous CS mouse models constructed using traditional gene editing techniques faced issues such as low targeting efficiency, extended lineage cycles, and inconsistent and unstable phenotypes. In this study, a CRISPR/Cas9-mediated strategy was employed to induce a functional augmentation of the Fgfr2 point mutation in mice. Various techniques, including bone staining, micro-CT, histological methods, and behavioral experiments, were employed to systematically examine and corroborate phenotypic disparities between mutant mice (Fgfr2C361Y/+) and their wild-type littermates. Confirmed via PCR-Sanger sequencing, we successfully induced the p.Cys361Tyr missense mutation in the Fgfr2 IIIc isoform of the extracellular domain (corresponding to the p.Cys342Tyr mutation in humans) based on Fgfr2-215 transcript (ENSMUST00000122054.8). Fgfr2C361Y/+ mice exhibited characteristics consistent with the phenotypic features associated with CS, including skull-vault craniosynostosis, skull deformity, shallow orbits accompanied by exophthalmos, midface hypoplasia with malocclusion, and shortened skull base, notably without any apparent limb defects. Furthermore, mutant mice displayed behavioral abnormalities encompassing deficits in learning and memory, social interaction, and motor dysfunction, without anxiety-related disorders. Histopathological examination of the hippocampal region revealed structural abnormalities, suggesting possible brain development impairment secondary to craniosynostosis. In conclusion, we constructed a novel gene-edited Fgfr2C361Y/+ mice strain based on CRISPR/Cas9, which displayed skull and behavioral abnormalities, serving as a new model for studying genetic molecular mechanisms and exploring treatments for CS. KEY MESSAGES: CRISPR/Cas9 crafted a Crouzon model by enhancing Fgfr2-C361Y in mice. Fgfr2C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration.