👤 Akira Meguro

Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high recurrence and poor survival, accounting for the majority of bladder cancer-related deaths. A subset of MIBC harbors FGFR1 amplification or overexpression, associated with increased proliferation and poor prognosis. Although the pan-FGFR inhibitor erdafitinib has demonstrated clinical benefit in patients with FGFR3/FGFR2 alterations, primarily in non-MIBC, its efficacy is limited by resistance and toxicity. Moreover, its effectiveness in FGFR1-driven MIBC remains unclear. To address this gap, we investigated erdafitinib response and resistance mechanisms in JMSU1 cells, a model of FGFR1-amplified MIBC. While erdafitinib initially suppressed tumor growth, prolonged treatment led to resistance, characterized by persistent activation of ERK, AKT, and STAT1 signaling pathways. Mechanistic studies identified MET activation, driven by MET gene amplification, as a key driver of resistance. Notably, exogenous hepatocyte growth factor (HGF) not only induced resistance but also accelerated the emergence of MET-amplified, HGF-independent subpopulations under drug pressure. We also identified SHP2 as a critical mediator of FGFR1-driven ERK activation in parental cells. In resistant cells, MET activation enhanced SHP2-ERK signaling through the adaptor protein GAB1, reinforcing the resistant phenotype. Combined inhibition of FGFR1 and MET significantly suppressed tumor growth in resistant cells. These findings establish MET amplification and GAB1-SHP2 signaling as central mediators of erdafitinib resistance in FGFR1-amplified MIBC and support dual FGFR1/MET targeting as a promising therapeutic strategy. Show less

Metformin, an AMP-activated protein kinase activator used to treat diabetes mellitus, has recently attracted attention as a promising anti-fibrotic agent. However, its anti-fibrotic effects on pleural fibroelastosis remain unknown. We induced mouse pleural fibroelastosis by intra-pleural coadministration of bleomycin and carbon and evaluated its validity as a preclinical model for human pleural fibrosis. We assessed the expression of the myofibroblast surface marker CD90 in the fibrotic pleura and the effects of metformin Show less

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS) with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA) that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs) in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group) and 53 type 1 AIP patients without (B group). The mean values of IgG and IG4 were both significantly different (P<0.05) between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001) were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021]) and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]). Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P = 0.00062, Pc = 0.003, OR = 2.98, 95%CI = 1.58–5.65) in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P = 0.00015, OR = 3.38, 95%CI = 1.77–6.45). In the LOC101928923 gene, the frequency of the minor T allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C allele of MPPED2 rs514644 carried a significantly increased risk of complications [corrected].These four genes may be linked with the onset of lachrymal/salivary gland lesions in type 1 AIP patients and require further study. Show less