佐谷 秀行

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.

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>

Poor survival of patients with osteosarcoma means that novel therapeutic targets are needed. A previously developed osteosarcoma mouse model revealed that HIF‑1 target genes are upregulated under anchorage‑independent growth conditions. HIF‑1α is highly expressed at the hypoxic invasion front in vivo. Knockout of HIF‑1α attenuates cell growth under hypoxic and non‑adherent conditions in vitro, as well as growth of primary and metastatic osteosarcoma in C57BL/6 mice, suggesting key roles for HIF‑1α in osteosarcoma progression. However, tumors with a rich vasculature develop in the absence of HIF‑1α. Thus, the HIF‑independent survival pathways on which HIF‑KO clones depend needs to be identified. The present study revealed that expression of glycolysis‑related genes, which are targets of HIF, decreased in HIF‑KO clones, but the sensitivity of each clone to inhibitors varied: Some were less sensitive than HIF wild‑type cells under hypoxic conditions. Compound screening revealed that the pathways upon which KO clones depend for survival differ. Indeed, inhibiting the mitochondrial electron transport chain, PI3K or mTOR further reduced growth of KO clones under hypoxic conditions, although one clone was less sensitive to these treatments and retained high proliferation capacity under hypoxic conditions. This clone was extremely sensitive to inhibition of the mevalonate synthesis pathway, suggesting that this might be the mechanism underlying resistance to HIF‑targeted therapies. Thus, although HIF‑1 is an attractive therapeutic target for osteosarcoma, it is necessary to identify and inhibit heterogenous HIF‑independent pathways upon which individual tumor cells rely.

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.

The clinical significance of comprehensive genomic profiling (CGP) has been established in metastatic castration-resistant prostate cancer (PC). However, the role of genomic profiling in localized PC remains unclear. In this exploratory study, we evaluated somatic genomic alterations in localized PC using an in-house CGP platform to examine their associations with biochemical recurrence (BCR) and recurrence-free survival (RFS) after radical prostatectomy. DNA extracted from surgical specimens of 314 patients with localized PC was analyzed for alterations in 164 cancer-related genes. Six genes (PTEN, BRCA2, POLD1, ERBB3, MYC, and SETD2) were more frequently altered in patients who developed BCR in exploratory analyses. Patients harboring alterations in any of these genes (n = 96) showed higher pathological T stage, increased BCR rates (27.1% vs. 6.4%), and inferior RFS compared with alteration-negative patients (n = 218; p < 0.001). In multivariate analysis, the presence of these alterations was independently associated with worse RFS. Among individual genes, BRCA2 alteration, and particularly BRCA2-SETD2 co-alteration, were associated with unfavorable outcomes, although the latter finding was based on a limited number of cases. In patients who developed BCR, alterations were associated with shorter PSA doubling time and poorer outcomes after salvage radiotherapy, particularly in margin-negative cases; however, these subgroup analyses were based on small numbers and should be interpreted as hypothesis-generating. These findings suggest that somatic genomic alterations identified at prostatectomy are associated with early recurrence in localized PC. Further validation in independent cohorts is required to determine whether genomic profiling may contribute to future risk stratification and management strategies.