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Despite the wide range of diagnostic and therapeutic methods, breast cancer is responsible for many deaths each year. One of the original and novel cancer therapeutic approaches is gene therapy based on recombinant adeno-associated viral vectors. Among the molecular factors with the potential to become useful diagnostic biomarkers, microRNA (miRNA) molecules are being considered for personalized therapies. The aim of the study was to examine the utility of miRNA profiling in the design of personalized recombinant adeno-associated virus (rAAV)-based gene therapy for breast cancer patients. The analysis of 754 miRNAs in 7 breast cancer samples and control samples was performed using real-time polymerase chain reaction (PCR) based on TaqMan® Low-density Array (TLDA) cards. Online repositories were used to explore the relationship between miRNAs and genes encoding rAAV receptors (KIAA0319L, HSPG2, FGFR1, c-MET, PDGFRA, ITGB5, and RPSA). Then, we performed a comparative analysis of the results to examine the possibility of using miRNA profiling in the design of rAAV-based therapeutic protocols. Fifty-two percent of tested miRNAs were noted in at least 1 analyzed breast cancer and control tissue. Thirteen miRNAs were selected due to being outliers in the tested samples. In total, 155 miRNAs targeted genes encoding rAAV receptors in the tested samples (29 miRNAs for KIAA0319L, 60 miRNAs for c-MET, 31 miRNAs for HSPG2, 43 miRNAs for FGFR1, 36 miRNAs for PDGFRA, 18 miRNAs for RPSA, and 25 miRNAs for ITGB5). The expression of the selected miRNAs was not homogeneous across the 7 samples. Profiling of microRNA could be a significant factor in the design of rAAV-based personalized gene therapy for breast cancer patients. Show less

Approved fibroblast growth factor receptor (FGFR) inhibitors include erdafitinib, pemigatinib, and futibatinib. We review the most common toxicities associated with FGFR inhibitors and provide practical advice regarding their management. Hyperphosphatemia can be managed with careful monitoring, dose reduction or interruption, a prophylactic low-phosphate diet, and phosphate-lowering therapy. Ocular adverse events (AEs) are managed by withholding or adjusting the dose of the FGFR inhibitor. Dermatologic AEs include alopecia, which can be managed with minoxidil, and dry skin, which can be treated with moisturizers. Hand-foot syndrome can be prevented by lifestyle changes and managed with moisturizing creams, urea, or salicylic acid. Among gastrointestinal AEs, diarrhea may be managed with loperamide; stomatitis can be managed with baking soda rinses, mucosa-coating agents, and topical anesthetics; and dry mouth may be alleviated with salivary stimulants. Most FGFR inhibitor-associated toxicities are manageable with prophylactic measures and treatments; proactive monitoring is key to ensuring optimal clinical benefits. Show less

Closed spinal dysraphisms are poorly understood malformations classified as neural tube (NT) defects. Several, including terminal myelocystocele, affect the distal spine. We have previously identified a NT closure-initiating point, Closure 5, in the distal spine of mice. Here, we document equivalent morphology of the caudal-most closing posterior neuropore (PNP) in mice and humans. Closure 5 forms in a region of active FGF signalling, and pharmacological FGF receptor blockade impairs its formation in cultured mouse embryos. Conditional genetic deletion of Fgfr1 in caudal embryonic tissues with Cdx2Cre diminishes neuroepithelial proliferation, impairs Closure 5 formation and delays PNP closure. After closure, the distal NT of Fgfr1-disrupted embryos dilates to form a fluid-filled sac overlying ventrally flattened spinal cord. This phenotype resembles terminal myelocystocele. Histological analysis reveals regional and progressive loss of SHH- and FOXA2-positive ventral NT domains, resulting in OLIG2 labelling of the ventral-most NT. The OLIG2 domain is also subsequently lost, eventually producing a NT that is entirely positive for the dorsal marker PAX3. Thus, a terminal myelocystocele-like phenotype can arise after completion of NT closure with localised spinal mis-patterning caused by disruption of FGFR1 signalling. Show less

There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1-FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to Show less

Germ cell tumors (GCT) might undergo transformation into a somatic-type malignancy (STM), resulting in a cell fate switch to tumors usually found in somatic tissues, such as rhabdomyosarcomas or adenocarcinomas. STM is associated with a poor prognosis, but the molecular and epigenetic mechanisms triggering STM are still enigmatic, the tissue-of-origin is under debate and biomarkers are lacking. To address these questions, we characterized a unique cohort of STM tissues on mutational, epigenetic and protein level using modern and high-throughput methods like TSO assays, 850k DNA methylation arrays and mass spectrometry. For the first time, we show that based on DNA methylation and proteome data carcinoma-related STM more closely resemble yolk-sac tumors, while sarcoma-related STM resemble teratoma. STM harbor mutations in FGF signaling factors (FGF6/23, FGFR1/4) highlighting the corresponding pathway as a therapeutic target. Furthermore, STM utilize signaling pathways, like AKT, FGF, MAPK, and WNT to mediate molecular functions coping with oxidative stress, toxin transport, DNA helicase activity, apoptosis and the cell cycle. Collectively, these data might explain the high therapy resistance of STM. Finally, we identified putative novel biomarkers secreted by STM, like EFEMP1, MIF, and DNA methylation at specific CpG dinucleotides. Show less

Fibroblast growth factor receptor (FGFR) gene family alterations are found in several cancers, indicating their importance as potential therapeutic targets. The FGFR-tyrosine kinase inhibitor (TKI) pemigatinib has been introduced in the treatment of advanced cholangiocarcinoma and more recently for relapsed or refractory myeloid/lymphoid neoplasms with FGFR2 and FGFR1 rearrangements, respectively. Several clinical trials are currently investigating the possible combination of pemigatinib with immunotherapy. In this study, we analyzed the biological and molecular effects of pemigatinib on different cancer cell models (lung, bladder, and gastric), which are currently objective of clinical trial investigations. NCI-H1581 lung, KATO III gastric and RT-112 bladder cancer cell lines were evaluated for FGFR expression by qRT-PCR and Western blot. Cell lines were treated with Pem and then characterized for cell proliferation, apoptosis, production of intracellular reactive oxygen species (ROS), and induction of senescence. The expression of microRNAs with tumor suppressor functions was analyzed by qRT-PCR, while modulation of the proteins coded by their target genes was evaluated by Western blot and mRNA. Descriptive statistics was used to analyze the various data and student's t test to compare the analysis of two groups. Pemigatinib exposure triggered distinct signaling pathways and reduced the proliferative ability of all cancer cells, inducing G1 phase cell cycle arrest and strong intracellular stress resulting in ROS production, senescence and apoptosis. Pemigatinib treatment also caused the upregulation of microRNAs (miR-133b, miR-139, miR-186, miR-195) with tumor suppressor functions, along with the downregulation of validated protein targets with oncogenic roles (c-Myc, c-MET, CDK6, EGFR). These results contribute to clarifying the biological effects and molecular mechanisms mediated by the anti-FGFR TKI pemigatinib in distinct tumor settings and support its exploitation for combined therapies. Show less

Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN. Show less

Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features. This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360 The presence of liver and/or lung metastases was associated with GAs of The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response. Show less

The present study involves synthesis a new series of α-aminophosphonates 2a-f and 4a-d derivatives in good yield with a simple workup via Kabachnik-Fields reaction in the presence of lithium perchlorate as Lewis acid catalyst. All the newly synthesized compounds were confirmed using various physical, spectroscopic, and analytical data. The in vitro anticancer activities of each compound were evaluated against colorectal carcinoma Colon cancer (HCT-116) and Epdermoid carcinoma (HEP2) and also Human lung fibroblast normal cell line (WI38) compared with Doxorubicin. The results showed that Compounds 2a, 4b and 4d exhibited more potent inhibitory activity for Epdermoid Carcinoma (HEP2) compared with doxorubicin. For colon carcinoma cells (HCT-116) Compounds 2a, 2d and 4b gave the strongest activity among all compounds compared with doxorubicin. Moreover, all designed structures were docked into the active site of VEGFR2 and FGFR1 proteins. The result reveals that compound 2b and have the strongest inhibitory activity of the VEGFR2 and FGFR1 proteins indicating that these substances might conceivably operate as VEGFR2 and FGFR1 inhibitors and hence might take role in anticancer activities with various binding interactions. The 3D-QSAR models produced strong statistical results since they were defined by PLS factors 4 and confirmed by parameters as R2, R2 CV, Stability, F-value, P-value, RMSE, Q2, and Pearson-r. Show less

Spinal cord injury (SCI) is a kind of traumatic nervous system disease caused by neuronal death, causing symptoms like sensory, motor, and autonomic nerve dysfunction. The recovery of neurological function has always been a intractable problem that has greatly distressed individuals and society. Although the involvement of iron-dependent lipid peroxidation leading to nerve cell ferroptosis in SCI progression has been reported, the underlying mechanisms remain unaddressed. Thus, this study aimed to investigate the potential of recombinant human FGF21 (rhFGF21) in inhibiting ferroptosis of nerve cells and improving limb function after SCI, along with its underlying mechanisms. In vivo animal model showed that FGFR1, p-FGFR1, and β-Klotho protein gradually increased over time after injury, reaching a peak on the third day. Moreover, rhFGF21 treatment significantly reduced ACSL4, increased GPX4 expression, reduced iron deposition, and inhibited ferroptosis. Meanwhile, rhFGF21 decreased cell apoptosis following acute spinal cord damage. In contrast, FGFR1 inhibitor PD173074 partially reversed the rhFGF21-induced therapeutic effects. Overall, this work revealed that rhFGF21 activates the FGFR1/β-Klotho pathway to decrease ferroptosis of nerve cells, suggesting that FGF21 could be a new therapeutic target for SCI neurological rehabilitation. Show less

Histiocytic sarcoma (HS) is an incurable aggressive tumor, and no consensus has been made on the treatment due to its rare occurrence. Since dogs spontaneously develop the disease and several cell lines are available, they have been advocated as translational animal models. In the present study, therefore, we explored gene mutations and aberrant molecular pathways in canine HS by next generation sequencing to identify molecular targets for treatment. Whole exome sequencing and RNA-sequencing revealed gene mutations related to receptor tyrosine kinase pathways and activation of ERK1/2, PI3K-AKT, and STAT3 pathways. Analysis by quantitative PCR and immunohistochemistry revealed that fibroblast growth factor receptor 1 (FGFR1) is over-expressed. Moreover, activation of ERK and Akt signaling were confirmed in all HS cell lines, and FGFR1 inhibitors showed dose-dependent growth inhibitory effects in two of the twelve canine HS cell lines. The findings obtained in the present study indicated that ERK and Akt signaling were activated in canine HS and drugs targeting FGFR1 might be effective in part of the cases. The present study provides translational evidence that leads to establishment of novel therapeutic strategies targeting ERK and Akt signaling in HS patients. Show less

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for Show less

Vascular endothelial growth factor receptors (VEGFRs) have emerged as the most promising anti-angiogenic therapeutic targets for the treatment of recurrent glioblastomas (GBM). However, anti-VEGF treatments led to the high proportion of non-responder patients or non lasting clinical response and the tumor progression to the greater malignant stage. To overcome these problems, there is an utmost need to develop innovative anti-angiogenic therapies. In this study, we report the development of a series of new FGFR1 inhibitors. Among them, compound 4i was able to potently inhibit FGFR1 kinase activities both in vitro and in vivo. This compound displayed strong anti-angiogenic activity in HUVECs and anti-tumor growth and anti-invasion effects in U-87MG cell line. These results emphasize the importance of FGFR1-mediated signaling pathways in GBM and reveal that pharmacological inhibition of FGFR1 can enhance the anti-tumoral, anti-angiogenic and anti-metastatic efficiency against GBM. These data support targeting of FGFR1 as a novel anti-angiogenic strategy and highlight the potential of compound 4i as a promising anti-angiogenic and anti-metastatic candidate for GBM therapy. Show less

Dovitinib is a receptor tyrosine kinase inhibitor of VEGFR1-3, PDGFR, FGFR1/3, c-KIT, FLT3 and topoisomerase 1 and 2. The drug response predictor (DRP) biomarker algorithm or DRP-Dovitinib is being developed as a companion diagnostic to dovitinib and was applied retrospectively. Archival tumor samples were obtained from consenting patients in a phase 3 trial comparing dovitinib to sorafenib in renal cell carcinoma patients and the DRP-Dovitinib was applied. The biomarker algorithm combines the expression of 58 messenger RNAs relevant to the in vitro sensitivity or resistance to dovitinib, including genes associated with FGFR, PDGF, VEGF, PI3K/Akt/mTOR and topoisomerase pathways as well as ABC drug transport, and provides a likelihood score between 0-100%. The DRP-Dovitinib divided the dovitinib treated RCC patients into two groups, sensitive (n = 49, DRP score >50%) or resistant (n = 86, DRP score ≤ 50%) to dovitinib. The DRP sensitive population was compared to the unselected sorafenib arm (n = 286). Median progression-free survival (PFS) was 3.8 months in the DRP sensitive dovitinib arm and 3.6 months in the sorafenib arm (hazard ratio 0.71, 95% CI 0.51-1.01). Median overall survival (OS) was 15.0 months in the DRP sensitive dovitinib arm and 11.2 months in the sorafenib arm (hazard ratio 0.69, 95% CI 0.48-0.99). The observed clinical benefit increased with increasing DRP score. At a cutoff of 67% the median OS was 20.6 months and the median PFS was 5.7 months in the dovitinib arm. The results were confirmed in five smaller phase II trials of dovitinib which showed a similar trend. The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients. Show less

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity. Show less

Currently, FRS and CRS are the two predominant dryland rearing systems in the goose industry. However, the effects of these two systems on goose growth performance and health, as well as the underlying mechanisms, have not been fully clarified. Thus, this study aimed to compare growth performance and immune status, as well as investigate the genome-wide transcriptomic profiles of spleen in geese, between CRS and FRS at 270 d of age. Phenotypically, the body weight and body size traits were higher in geese under FRS, while the weight and organ index of spleen were higher in geese under CRS ( Show less

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency. Show less

Mantle cell lymphoma (MCL) is a lethal hematological malignancy with a median survival of 4 years. Its lethality is mainly attributed to a limited understanding of clinical tumor progression and resistance to current therapeutic regimes. Intrinsic, prolonged drug treatment and tumor-microenvironment (TME) facilitated factors impart pro-tumorigenic and drug-insensitivity properties to MCL cells. Hence, elucidating neoteric pharmacotherapeutic molecular targets involved in MCL progression utilizing a global "unified" analysis for improved disease prevention is an earnest need. Using integrated transcriptomic analyses in MCL patients, we identified a Fibroblast Growth Factor Receptor-1 (FGFR1), and analyses of MCL patient samples showed that high FGFR1 expression was associated with shorter overall survival in MCL patient cohorts. Functional studies using pharmacological intervention and loss of function identify a novel MYC-EZH2-CDKN1C axis-driven proliferation in MCL. Further, pharmacological targeting with erdafitinib, a selective small molecule targeting FGFRs, induced cell-cycle arrest and cell death in-vitro, inhibited tumor progression, and improved overall survival in-vivo. We performed extensive pre-clinical assessments in multiple in-vivo model systems to confirm the therapeutic potential of erdafitinib in MCL and demonstrated FGFR1 as a viable therapeutic target in MCL. Show less

We report a case of a 20-year-old man who presented with splenomegaly, hyperleukocytosis, anemia, and thrombocytopenia. A diagnosis of acute myeloid leukemia (AML) with LRRFIP1::FGFR1 rearrangement with complex karyotype was determined. Chromosome analysis showed a male karyotype: 46,XY,i(1)(q10),t(2;8)(q37;p11.2),der(5)t(1;5) (p22;q13)[17]46,XY[3]. Fluorescence in situ hybridization (FISH) analysis using the Cytocell FGFR1 break apart/amplification probe detected FGFR1 rearrangement with t(2:8) in 126/200 cells analyzed. Other FISH probes including 1p36/ 1q25 probes, del(5q) deletion probe, TLX3 break apart probe, and PDGFRB break apart probe were also utilized to confirm the other karyotypic abnormalities. Next-generation sequencing (NGS) SureSelectXT Custom DNA Target Somatic Detection detected RUNX1 gene mutation. NGS Archer FusionPlex (RNA) confirmed the LRRFIP1::FGFR1 rearrangement. This is the second reported case of AML with LRRFIP1::FGFR1 rearrangement and the first with a complex karyotype. Show less

Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care. Show less

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases. Show less

Tendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where entheses can be found. We used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences. Show less

Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action. Whether other FGFs possess similar therapeutic benefits is currently unknown. Here, we show that icvFGF4 also elicits a sustained antidiabetic effect in both male db/db mice and diet-induced obese mice by activating FGF receptor 1 (FGFR1) expressed in glucose-sensing neurons within the mediobasal hypothalamus. Specifically, FGF4 excites glucose-excited (GE) neurons while inhibiting glucose-inhibited (GI) neurons. Moreover, icvFGF4 restores the percentage of GI neurons in db/db mice. Importantly, intranasal delivery of FGF4 alleviates hyperglycemia in db/db mice, paving the way for non-invasive therapy. We conclude that icvFGF4 holds significant therapeutic potential for achieving sustained remission of T2D. Show less

Glioblastoma is the most lethal brain cancer in adults. These incurable tumors are characterized by profound heterogeneity, therapy resistance, and diffuse infiltration. These traits have been linked to cancer stem cells, which are important for glioblastoma tumor progression and recurrence. The fibroblast growth factor receptor 1 (FGFR1) signaling pathway is a known regulator of therapy resistance and cancer stemness in glioblastoma. FGFR1 expression shows intertumoral heterogeneity and higher FGFR1 expression is associated with a significantly poorer survival in glioblastoma patients. The role of FGFR1 in tumor invasion has been studied in many cancers, but whether and how FGFR1 mediates glioblastoma invasion remains to be determined. Here, we investigated the distribution and functional relevance of FGFR1 and FGFR2 in human glioblastoma xenograft models. We found FGFR1, but not FGFR2, expressed in invasive glioblastoma cells. Loss of FGFR1, but not FGFR2, significantly reduced cell migration in vitro and tumor invasion in human glioblastoma xenografts. Comparative analysis of RNA-sequencing data of FGFR1 and FGFR2 knockdown glioblastoma cells revealed a FGFR1-specific gene regulatory network associated with tumor invasion. Our study reveals new gene candidates linked to FGFR1-mediated glioblastoma invasion. Show less

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor tyrosine kinase (RTK), is often upregulated in various cancers. This study aimed to validate PTK7 as a target for breast cancer (BC) and investigate its oncogenic signaling mechanism. BC tissue analysis showed significantly elevated PTK7 mRNA levels, especially in refractory triple-negative breast cancer (TNBC) tissues, compared with normal controls. Similarly, BC cell lines exhibited increased PTK7 expression. Knockdown of PTK7 inhibited the proliferation of T-47D and MCF-7 hormone-receptor-positive BC cell-lines and of HCC1187, MDA-MB-231, MDA-MB-436, and MDA-MB-453 TNBC cells. PTK7 knockdown also inhibited the adhesion, migration, and invasion of MDA-MB-231, MDA-MB-436, and MDA-MB-453 cells, and reduced the phosphorylation levels of crucial oncogenic regulators including extracellular signal-regulated kinase (ERK), Akt, and focal adhesion kinase (FAK). Furthermore, PTK7 interacts with fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR) expressed in MDA-MB-231 cells. Knockdown of PTK7 decreased the growth-factor-induced phosphorylation of FGFR1 and EGFR in MDA-MB-231 cells, indicating its association with RTK activation. In conclusion, PTK7 plays a significant role in oncogenic signal transduction by enhancing FGFR1 and EGFR activation, influencing BC tumorigenesis and metastasis. Hence, PTK7 represents a potential candidate for targeted BC therapy, including TNBC. Show less

Genomic alterations in fibroblast growth factor receptor (FGFR) genes have been linked to a reduced response to immune checkpoint inhibitors. Some of the immune microenvironment of urothelial bladder cancer (UBC) could be distorted because of the inhibition of interferon signaling pathways. We present a landscape of FGFR genomic alterations in distorted UBC to evaluate the immunogenomic mechanisms of resistance and response. There were 4035 UBCs that underwent hybrid, capture-based comprehensive genomic profiling. Tumor mutational burden was determined in up to 1.1 Mbp of sequenced DNA and microsatellite instability was determined in 114 loci. Programmed death ligand expression in tumor cells was assessed by immunohistochemistry (Dako 22C3). The FGFR tyrosine kinases were altered in 894 (22%) UBCs. The highest frequency of alterations was in FGFR genomic alterations with FGFR3 at 17.4% followed by FGFR1 at 3.7% and FGFR2 at 1.1%. No FGFR4 genomic alterations were identified. The age and sex distribution were similar in all groups. Urothelial bladder cancers that featured FGFR3 genomic alterations were associated with lower driver genomic alterations/tumors. 14.7% of the FGFR3 genomic alterations were FGFR3 fusions. Other findings included a significantly higher frequency of ERBB2 amplification in FGFR1/2-altered UBCs compared with FGFR3-altered UBCs. Urothelial bladder cancers with FGFR3 genomic alterations also had the highest frequency of the activating mTOR pathway. FGFR3-altered UBCs also featured significantly higher frequencies of biomarkers associated with a lack of response to immune checkpoint inhibitors including a lower tumor mutational burden, lower programmed death-ligand 1 expression, and higher frequencies of genomic alterations in MDM2. Also linked to IO drug resistance, CDKN2A/B loss and MTAP loss were observed at a higher frequency in FGFR3-driven UBC. An increased frequency of genomic alterations is observed in UBC FGFR. These have been linked to immune checkpoint inhibitor resistance. Clinical trials are needed to evaluate UBC FGFR-based biomarkers prognostic of an immune checkpoint inhibitor response. Only then can we successfully incorporate novel therapeutic strategies into the evolving landscape of UBC treatment. Show less

Many studies have illustrated the significance of long noncoding RNAs in oncogenesis and promotion of breast cancer (BC). However, the biological roles of CCDC183 antisense RNA 1 (CCDC183-AS1) in BC have rarely been characterized. Thus, we explored whether CCDC183-AS1 is involved in the malignancy of BC and elucidated the possible underlying mechanisms. Our data confirmed elevated CCDC183-AS1 expression in BC, which was associated with poor clinical outcomes. Functionally, knocking down CCDC183-AS1 hampered cell proliferation, colony formation, migration, and invasion in BC. Additionally, the absence of CCDC183-AS1 restrained tumor growth Show less