滝本 哲也

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies and is characterized by pronounced phenotypic plasticity, metabolic adaptation, and therapeutic resistance within a dense and desmoplastic tumor microenvironment. Although transcriptional deregulation has been extensively investigated, post-transcriptional regulation, particularly the control of mRNA stability, has emerged as a critical and previously underexplored contributor to PDAC progression. RNA-binding proteins (RBPs), together with cis-regulatory RNA elements and epitranscriptomic modifications such as N6-methyladenosine (m6A), form interconnected regulatory networks that dynamically modulate mRNA turnover and thereby shape protein output in response to microenvironmental stress. By selectively stabilizing transcripts encoding epithelial–mesenchymal transition (EMT) regulators, metabolic enzymes, and stress-response factors, these networks promote reversible, non-genetic adaptation without requiring permanent genetic alterations. This regulatory flexibility supports invasion, therapeutic tolerance, and intratumoral heterogeneity under hypovascular and nutrient-limited conditions. Recent advances further suggest that targeting mRNA stability through small molecules and RNA-directed strategies may provide new therapeutic opportunities in PDAC. In this review, we summarize current insights into post-transcriptional mechanisms regulating mRNA stability in PDAC, highlight key knowledge gaps, and discuss their potential translational implications.

Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion within each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, as well as their relationship to photoreceptor function, remain incompletely understood. Here, we investigated the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in rod photoreceptor cells. Rod-specific ablation of MFN1 and MFN2 resulted in near-complete and uniform mitochondrial fragmentation by 1 month of age, indicating that mitochondrial fusion is required for the development and maintenance of photoreceptor cell-specific mitochondrial architecture. At this stage, the layer structures of the retina examined by light microscopy appeared largely unaffected. Despite the absence of overt structural degeneration, electroretinography revealed early functional impairment, including reduced a-wave amplitudes and attenuation of the c-wave, indicating compromised rod photoreceptor activity and disrupted photoreceptor–RPE interactions. This was followed by progressive photoreceptor cell degeneration observed at 2 and 3 months of age. MFN1/2 ablation was also associated with changes in proteins involved in glycolysis, oxidative phosphorylation, and β-oxidation, along with activation of cellular stress pathways, including ER stress and the unfolded protein response. While total retinal ATP levels were only modestly reduced at early stages, these findings are consistent with alterations in metabolic homeostasis. Together, our findings demonstrate that MFN1 and MFN2 are required for specialized mitochondrial architecture in rod photoreceptor cells, and that their loss is associated with molecular remodeling and early functional deficits, preceding progressive degeneration.

Abstract <p> Coding variations do not significantly contribute to tumor aggressiveness in meningiomas except for rare alterations in CDKN2A and TERT . The aim of this study was to investigate specific molecular pathways as potential therapeutic targets. A discovery cohort of 35 meningiomas, including 26 high-grade tumors, was investigated for genetic alterations and gene expression profiling, and analyzed by unsupervised hierarchical clustering, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). The results were validated by OncoPrint analyses in a larger dataset published previously. The efficacy of an EZH2 inhibitor was evaluated in multiple meningioma cell lines. Tumors in the discovery cohort were classified into three clusters (Cluster M: Low, Mid, High) using hierarchical clustering based on genes differentially expressed across CNS WHO grades. These clusters correlated with overall survival and WHO grade. GSEA between the subgroups of Cluster M demonstrated that meningiomas gain aggressiveness through the downregulation of gene sets associated with the immune response (Low→Mid), and subsequently by the upregulation of those associated with cell cycle and cell proliferation (Mid→High). These results were corroborated by GSVA based on the enrichment score of the Hallmark gene sets as well as hierarchical clustering based on copy number losses, with enrichment of the E2F target and MYC target gene sets in high-grade clusters. OncoPrint analyses in the published dataset showed that the most aggressive type of meningiomas is characterized by upregulation of EZH2 as well as E2F1, but not MYC, in combination with NF2 alterations. Meningioma cell growth was suppressed by an EZH2 inhibitor with possible correlation with EZH2 expression. Meningiomas with NF2 alterations exhibit distinct biological behaviors depending on the expression of EZH2 and E2F1, and aggressive meningiomas are characterized by the upregulation of these pathways in combination with NF2 alterations. EZH2 is a pivotal therapeutic target for high-grade meningiomas. </p>

ABSTRACT BRAF p.V600E‐mutant gliomas and glioneuronal tumors comprise a wide clinicopathological spectrum, yet the relationship between genomic alteration burden and histological grade remains incompletely defined. We analyzed 15 BRAF p.V600E‐mutant gliomas and glioneuronal tumors across histological grades using the PleSSision Rapid sequencing platform. Single‐nucleotide variants (SNVs) and copy‐number alterations were assessed in parallel to characterize genomic alteration profiles. Low‐grade tumors generally exhibited limited genomic alterations; however, a subset of low‐grade tumors showed increased numbers of SNVs. High‐grade tumors demonstrated more extensive genomic alterations, characterized predominantly by copy‐number gains. A trend toward increased copy‐number gains with higher WHO grade was observed. Homozygous deletion of CDKN2A was observed in pleomorphic xanthoastrocytoma, including both CNS WHO grade 2 and grade 3 tumors, and epithelioid glioblastoma. These findings indicate substantial genomic heterogeneity among BRAF p.V600E‐mutant gliomas and glioneuronal tumors. While low‐grade tumors are generally genomically quiet, a subset shows increased alterations, and high‐grade tumors tend to acquire copy‐number changes, highlighting the limitations of genomic event counts alone as a surrogate for malignant potential.