Ribonucleic acid (RNA) modifications, once viewed as static structural features, are now recognized as dynamic regulators of the ‘epitranscriptome’ that shape RNA fate. In cancer, dysregulation of RNA-modification writers, erasers, and readers reprograms RNA metabolism and translation, promoting tumorigenesis, metastasis, therapy resistance, and immune evasion. Across messenger RNAs, ribosomal RNA (rRNAs), transfer (tRNAs), and diverse non-coding RNAs, aberrant modification patterns drive alternative splicing, generate onco-ribosomes, enforce codon-biased translation, and remodel gene-expression networks in a context-dependent manner. This review summarizes how major RNA modifications—including m6A, m5C, pseudouridine, inosine, and ac4C—and their regulators contribute to cancer biology, together with disease-associated changes in rRNA, tRNA, and regulatory non-coding RNAs. We then discuss emerging diagnostic and prognostic biomarkers, druggable nodes within the epitranscriptomic machinery, and combination strategies that integrate RNA-modification targeting with existing therapies and immunotherapy. Finally, we outline key technologies for mapping RNA modifications, comparing mass spectrometry and NGS-based chemical or antibody-enrichment approaches with the expanding capabilities of nanopore direct RNA sequencing. Recent advances in nanopore direct RNA sequencing technologies, leveraging new chemistry (e.g. RNA004) and deep-learning basecallers (e.g. Dorado), increasingly enable single-molecule, multi-modification profiling, accelerating discovery despite inherent technical challenges. Collectively, biological, clinical, and technological progress is transforming the epitranscriptome into a tractable dimension of cancer biology and a promising source of future biomarkers and RNA-targeted precision therapies.

Abstract Background: Peptide receptor radionuclide therapy (PRRT) is an internal radiotherapy for somatostatin receptor (SSTR)-positive neuroendocrine tumor (NET). The tumor microenvironment, particularly cytotoxic T lymphocyte (CTL), is a key determinant of tumor behavior, treatment response, and prognosis, but NET typically shows a “cold” immune microenvironment with sparse immune-cell infiltration, which may contribute to the limited efficacy of ICI-based therapies. External beam radiotherapy can activate systemic antitumor immunity and occasionally induce abscopal effects, in which irradiation of a primary lesion leads to shrinkage of both irradiated and distant metastatic sites; however, the influence of PRRT on systemic immunity has scarcely been studied. We hypothesized that PRRT modulates systemic immunity in NET patients and investigated changes in circulating cytokines. Methods: We analyzed changes in serum cytokine levels in NET patients treated with PRRT at Yokohama City University. Twelve paired serum samples from 9 patients were collected before and after PRRT and analyzed with a 36-plex cytokine array. Results: Of the 9 patients, 7 were undergoing their first PRRT course and 2 a second course (retreatment after a prior four-administration PRRT course that had achieved at least partial response with ≥1.5 year of disease control). Primary sites were pancreas (n=6), rectum (n=1), lung (n=1), and thymus (n=1), and target lesions were in the liver (n=7), bone (n=2), primary site (n=1), lymph node (n=1), and peritoneum (n=1). Twelve serum pairs comprised 10 pre- and post-individual PRRT administrations and 2 pre- and post-full-course pairs. Of the 36 examined cytokines, only 12 were detectable. Among these, CD154 showed more than 2-fold changes in 7 pairs, with 6 showing downregulation and 1 showing upregulation after PRRT. IL-1ra was also upregulated in 3 pairs. Conclusion: We found that PRRT is associated with systemic changes in circulating cytokines in NET patients, notably modulation of CD154 and IL-1ra. These data suggest that PRRT may influence host antitumor immunity; larger studies are required to elucidate the mechanisms and clinical significance of these immune changes. Citation Format: Eriko Katsuta, Takuto Nobuhiro, Masaru Takeuchi, Satoshi Matsui, Asano Daisuke, Ishikawa Yoshiya, Hiroki Ueda, Keiichi Akahoshi, Noritoshi Kobayashi, Yasushi Ichikawa, Daisuke Ban. Peripheral immune signatures associated with peptide receptor radionuclide therapy in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7754.

BACKGROUND:For anatomically resectable pancreatic cancer, a "biological borderline resectable" concept based on carbohydrate antigen 19-9 (CA19-9) elevation or suspected nodal metastasis is proposed; however, preoperative nodal staging remains imprecise. We evaluated whether embryologic tumor location combined with CA19-9 can stratify biological risk of resectable pancreatic head cancer (RPHC). METHODS:We retrospectively analyzed 78 patients who underwent pancreaticoduodenectomy for RPHC between January 2010 and June 2024. Embryologic tumor location was determined from preoperative imaging and categorized as ventral or dorsal pancreas. The optimal pretreatment CA19-9 cutoff for overall survival was determined using maximally selected rank statistics. Associations between embryologic tumor location, CA19-9, and survival outcomes were examined, and predictors of recurrence were identified using Cox proportional hazards models. RESULTS:An optimal CA19-9 cutoff of 150 U/mL was identified. Dorsal tumors were associated with shorter recurrence-free survival (RFS) (p = 0.004) and overall survival (OS) (p = 0.048), while CA19-9 levels > 150 U/mL were associated with worse RFS (p = 0.015) and OS (p < 0.001). On multivariate analysis, dorsal location (hazard ratio [HR] 2.30, p = 0.035) and CA19-9 levels > 150 U/mL (HR 1.93, p = 0.024) remained independent predictors of recurrence, whereas clinical nodal status was not (HR 1.91, p = 0.149). A three-tier classification combining tumor location and CA19-9 stratified patients by RFS (p = 0.001) and OS (p < 0.001), with dorsal/high-CA19-9 tumors showing the poorest outcomes. CONCLUSIONS:Integrating embryologic tumor location with CA19-9 levels may refine risk stratification in RPHC and help guide treatment strategies.

INTRODUCTION:Metastatic tumors to the pancreas account for approximately 2% of all pancreatic malignancies, and pancreatic metastasis from distal cholangiocarcinoma is extremely rare. Differentiating pancreatic metastasis of cholangiocarcinoma from primary pancreatic cancer is often difficult, as both typically present as adenocarcinoma with similar immunohistochemical features. CASE PRESENTATION:A 65-year-old man underwent subtotal stomach-preserving pancreatoduodenectomy (SSPPD) for distal cholangiocarcinoma. He was diagnosed with pT3N0M0, Stage IIB according to the UICC TNM classification, 8th edition. Seven years after surgery, a routine blood test revealed an elevated serum carbohydrate antigen 19-9 level. Abdominal MRI and CT demonstrated 2 small masses, each approximately 10 mm in diameter, in the remnant pancreas without evidence of distant metastasis. Both lesions were diagnosed as adenocarcinoma by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), suggesting either pancreatic metastases from distal cholangiocarcinoma or primary pancreatic cancer in the remnant pancreas. Completion total pancreatectomy with splenectomy was therefore performed. Histopathological examination showed that both lesions in the remnant pancreatic tail were morphologically similar to the initial cholangiocarcinoma. However, the possibility of primary pancreatic cancer could not be completely excluded. Comprehensive genomic profiling (CGP) of the initial cholangiocarcinoma and the remnant pancreatic tumor revealed a shared TP53 H214R alteration, supporting the diagnosis of pancreatic metastases from distal cholangiocarcinoma. In addition, CGP identified BRCA1 loss and an FGFR3 alteration in the remnant pancreatic tumor as potentially actionable findings, although their therapeutic relevance in cholangiocarcinoma remains uncertain. CONCLUSIONS:We report a rare case of multiple pancreatic metastases occurring 7 years after resection of distal cholangiocarcinoma. Evaluation of genetic alterations provided supportive evidence to aid in distinguishing metastatic disease from primary pancreatic cancer in the remnant pancreas. In addition, these findings also suggested potentially relevant therapeutic targets.

Background:Surgical resection for neuroendocrine liver metastasis (NELM) is the key to long survival; however, the indications remain unclear due to the high recurrence rate. We aimed to identify candidates who would benefit from surgical resection for NELM. Methods:Patients with NELM treated at our institution from January 2005 to December 2020 were included. Neuroendocrine carcinoma (NEC) was excluded. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were analyzed. The cut-off value for the number of NELM predicting poor RFS was determined by minimum p-value approach. Results:Of the total 126 patients, 67 patients underwent liver resection. The median follow-up time from the date of initial diagnosis of NELM was 4.3 years. Surgical resection and NET-G1/2 were associated with good OS in multivariate analysis (p < 0.001). In patients underwent R0/1 resection (n = 44), NET-G3 [HR: 3.1 (95% CI 1.4-7.2)] and the number of NELM [HR: 1.1 (95% CI 1.0-1.1)] were associated with poor RFS in multivariate analysis. The optimal cut-off value for the number of NELM was calculated as 8. The median RFS for patients with 8 or more liver metastases or NET-G3 was 3.9 months, which was extremely short compared to patients with NET-G1/2 (13.8 months) and to those who had fewer than 8 liver metastases (19.1 months). Conclusion:This study suggests that fewer than 8 liver metastases and NET-G1/2 are indications for surgical resection in patients with NELM considering the RFS. Surgical resection for patients with 8 or more liver metastases or NET-G3 needs deliberate selection.

INTRODUCTION:Symptom control is sometimes as important as tumor burden control in patients with functional neuroendocrine tumors (NETs). The selective arterial calcium injection (SACI) test is widely used to localize functional NETs, particularly insulinomas and gastrinomas; however, its utility in adrenocorticotropic hormone (ACTH)-producing tumors (ACTHomas) remains unclear. We present a case of a pancreatic head ACTHoma with synchronous liver metastases in which the SACI test with venous sampling ("hormonal mapping") enabled a safe, staged curative resection. CASE PRESENTATION:A 42-year-old woman presented with features of Cushing's syndrome, including edema and weight gain. CT revealed a pancreatic head tumor with multiple liver metastases. Liver biopsy confirmed the diagnosis of NET, suggesting an ACTHoma. Hormonal mapping demonstrated that liver metastases, rather than the pancreatic tumor, were the predominant sources of ACTH secretion. To achieve hormonal control, we prioritized laparoscopic liver resection, followed by laparoscopic pancreatoduodenectomy three months later after confirming the absence of new metastatic lesions. At 21 months postoperatively, the patient remains recurrence-free. CONCLUSIONS:Hormonal mapping was effective in identifying hormone-producing lesions and guiding surgical strategies for ACTHomas with liver metastases.

In aging societies, neurodegenerative diseases, such as Alzheimer’s disease, are receiving attention. These diseases are primary targets for preemptive medicine, emphasizing the importance of early detection and preventive treatment before the onset of severe, treatment-resistant damages. However, there is a lack of comprehensive investigation of lesions and molecular targets in the entire organ, whereas spatial identification of early-stage lesions is potentially overlooked at the single-cell level. Here, we propose a novel approach, CWAS (whole body/organ cellome-wide association studies), which integrates and analyzes spatio-temporal cellular information across the entire mouse organ into a comprehensive organ cell atlas using tissue-clearing imaging technologies [1,2]. In our initial application to neurodegenerative models, we have been able to identify previously unreported neural degenerations at specific times and locations at the single-cell level. In addition, our time-series analysis in a mouse model of Alzheimer’s disease revealed the possible simultaneous onset of amyloid deposition and neurodegeneration, challenging the traditional amyloid hypothesis. Furthermore, we were able to identify unique multicellular inflammation networks surrounding neurodegenerative lesions in several disease models. Our findings establish the concept of “ spatial cellomics ” realized through spatially precise organ mapping and integrated multiomics analysis at the single-cell level. This approach shifts pathology, providing deeper insight into disease mechanisms and preventive strategies. References [1] Murakami TC, et al. Nat Neurosci . 2018;21(4):625-637. [2] Matsumoto K*, Mitani TT*, Horiguchi SA, et al*. (*equal contribution) Nat Protoc . 2019;14(12):3506-3537.

Advanced hepatic fibrosis is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC), and it is required to identify a key mediator involved in intratumoral fibrosis and HCC development. Transcriptomic analysis of 372 HCC samples using publicly available datasets revealed that SPP1 was significantly upregulated in fibrotic HCC tissues and associated with unfavorable outcomes. Immunohistochemical analysis of 103 HCC tissues and single-cell RNA sequencing (scRNA-seq) analysis of 228,564 live cells identified SPP1 overexpression in HCC cells, which strongly correlated with intratumoral fibrosis. In xenograft models, HCC cells with SPP1 overexpression (SPP1-OE) exhibited enhanced fibrosis and tumor growth. Coculture assay demonstrated that SPP1-OE cells stimulated hepatic stellate cells (HSCs), and gene set enrichment analysis and differential gene expression analysis elucidated the activation of the Hedgehog signaling pathway and upregulation of GLI1 in HSCs. Cell-cell interaction prediction analysis using scRNA-seq data suggested that SPP1-CD44 signaling transduction might contribute to HSC activation. Pharmacological inhibition of GLI1 with the SMO inhibitor vismodegib suppressed HSC activation in vitro and reduced fibrosis and tumor growth in vivo. These findings indicate that SPP1 promotes intratumoral fibrosis and HCC progression through the SPP1-CD44-GLI1 axis, highlighting its potential as a prognostic biomarker and therapeutic target. Inhibition of SPP1-CD44-Hedgehog signaling may provide a promising strategy to mitigate fibrosis and improve HCC patient outcomes.

Background: Systemic therapy is a standard treatment option for pancreatic neuroendocrine neoplasms (Pan-NENs) with unresectable or metastatic disease. Streptozocin (STZ)-based chemotherapy is considered a standard treatment option for tumors with a high Ki-67 index or for cases refractory to molecular targeted agents. More recently, the combination of capecitabine and temozolomide (CAPTEM) therapy has emerged as a new treatment option. Objectives: This study aimed to compare the efficacy, safety, and clinical outcomes between the STZ-based regimen and CAPTEM therapy in patients with unresectable or metastatic Pan-NENs. Design: This was a single-center retrospective study of histologically confirmed Pan-neuroendocrine tumor (NET) patients treated with either STZ-based regimens or CAPTEM between November 2015 and June 2024. Methods: We compared efficacy, safety, and clinical outcomes between the two regimens. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events were graded according to Common Terminology Criteria for Adverse Events version 5.0. The study was conducted in compliance with the STROBE guidelines. Results: Of the 371 patients diagnosed with Pan-NENs, 47 received STZ-based regimen and 21 received CAPTEM therapy. In the NET-G1/G2 patients, the STZ group showed a significantly higher tumor shrinkage rate compared to CAPTEM therapy. Although no significant differences were observed in progression-free survival (PFS) or overall survival between the two groups, subgroup analysis showed that the median PFS in the STZ group was significantly longer than that in the CAPTEM group in NET G1/G2 patients. Renal dysfunction was the main adverse event in the STZ regimen group, while gastrointestinal symptoms were common in the CAPTEM therapy group; however, both were manageable. Conclusion: Both STZ-based regimen and CAPTEM therapy are safe and effective treatment options for advanced Pan-NENs. STZ-based regimen was more beneficial in NET-G1/G2 patients, suggesting Ki-67 index and tumor grade may serve as indicators for treatment selection. Further prospective studies are warranted to validate these findings.

BACKGROUND & AIMS:Insulinomas are rare pancreatic neuroendocrine neoplasms (pan-NENs) characterized by inappropriate insulin secretion. Despite advances in imaging techniques, the reliable identification of insulin-secreting lesions remains challenging. In addition, medical treatment options are limited and have seen little development in recent years, highlighting the unmet need for improved diagnostic tools and therapeutic strategies. This study aimed to identify the molecular mechanisms underlying insulin hypersecretion in insulinomas. METHODS:We established a biobank of human insulinoma surgical specimens and matched organoids. Comprehensive transcriptomic analyses-including bulk RNA sequencing, single-cell RNA sequencing, quantitative polymerase chain reaction, and immunohistochemistry-were conducted to identify genes enriched in insulin-secreting components. Functional validation was performed using MIN6 cells, a xenograft mouse model, and long-term cultured human insulinoma organoids. RESULTS:We identified dedicator of cytokinesis 10 (DOCK10) as a gene selectively overexpressed in insulin-secreting components of insulinomas. DOCK10 knockdown impaired glucose-stimulated insulin secretion in both mouse insulinoma cells and patient-derived organoids. Inhibition of the downstream effector Cdc42 with ML141 reduced insulin hypersecretion and improved survival in a MIN6 xenograft mouse model. These findings uncover a previously unrecognized role of the DOCK10-Cdc42 axis in regulating insulin secretion in insulinoma. CONCLUSIONS:This study suggests that DOCK10 may serve as a diagnostic marker for insulin-secreting lesions and a potential therapeutic target in insulinoma. It provides mechanistic insights that may inform future strategies for precision diagnostics and treatment of functional pancreatic neuroendocrine tumors.