Background: Perineural invasion (PNI) is a key biological feature underpinning the high malignancy and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Lysine lactylation (Kla), a metabolite-stress-induced post-translational modification, plays crucial regulatory roles in diverse biological processes. The RNA methyltransferase NSUN2 is essential for cancer invasion and metastasis. However, the mechanisms by which NSUN2 contributes to lactylation-driven PNI in PDAC remain to be elucidated. Methods: We assessed tumor lactate / pan-lactylation, NSUN2 lactylation, and PNI in human PDAC cohorts with survival follow-up. Functional studies used PDAC cell lines for migration/invasion assays, dorsal-root-ganglion (DRG) co-culture, and neurite-outgrowth assays under lactate or enzymatic perturbations. Mechanistic interrogation combined NSUN2 knockout, CRISPR knock-in mutants at K692 (K692R/E), co-immunoprecipitation, RIP-seq, MeRIP-qPCR, and actinomycin-D chase to test mRNA binding, m5C modification, and stability of CDCP1/STC1. In vivo validation employed a sciatic nerve invasion model and a KPC genetically engineered mouse model to assess tumor-nerve infiltration and disease progression. Results: Lactylated NSUN2 is markedly upregulated in mice and human PDAC with more severe PNI, and is significantly associated with poorer prognosis. Functionally, inhibiting lactylation or blocking NSUN2 markedly attenuated tumor-nerve interactions and neural invasion. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC1 mRNA, enhanced their mRNA stability. Conclusions: This study identifies lactate-driven NSUN2 K692 lactylation as a key driver of perineural invasion in PDAC. We define a lactate-NSUN2-m5C-CDCP1/STC1 axis that links metabolic stress-induced lysine lactylation to mRNA methylation-dependent stabilization of pro-invasive transcripts, highlighting actionable therapeutic targets to restrain neural invasion and improve patient outcomes.

Given that pancreatic cancer (PC) is typically diagnosed at an advanced stage but is often preceded by new-onset diabetes mellitus (NODM), providing a window for early detection, we sought to develop and validate an interpretable machine-learning model integrated with multi-omics profiling to identify early biomarkers of NODM-associated PC. In a population-based cohort, individuals with NODM-associated PC and NODM without PC were identified and randomly divided (70:30) into training and validation sets after feature selection. Eight machine learning (ML) classifiers were compared using fivefold cross-validation, and model performance was evaluated in terms of discrimination, calibration, and decision curve–based clinical utility. We evaluated interpretability using the Shapley additive explanations (SHAP) analyses. Mechanistically, Olink proteomic profiling and metabolomics were analyzed through clinical classifications and model-defined risk strata. Categorical boosting achieved the best performance in the independent validation set (AUROC = 0.844). The NODM cohort was stratified into high- (n = 2,362) and low-risk (n = 5,030) groups, and internal validation together with SHAP analyses demonstrated consistent model performance and identified clinically interpretable predictors. Proteomic and metabolomic analyses under clinical and risk-based grouping identified 39 overlapping differentially expressed proteins and 145 overlapping metabolites with enriched across 11 shared KEGG pathways. Cross-platform validation highlighted PLTP, CRTAC1, and ITGAV as serum biomarkers with a strong potential for early NODM-PC detection. We developed an interpretable ML framework centered on NODM enables practical risk stratification for early PC detection by multi-omics and provides a pathway of ML-based triage followed by biomarker confirmation for earlier detection and diagnosis.

BACKGROUND:The application of the novel KRASG12D inhibitor in pancreatic ductal adenocarcinoma (PDAC) is currently hindered by adaptive resistance. Metabolic reprogramming is a hallmark of KRASG12D signalling, yet the mechanisms linking these alterations to immunosuppression and low therapeutic response are poorly defined. OBJECTIVE:To identify the key regulatory nodes connecting KRASG12D-driven metabolic adaptations to tumour microenvironment and develop a mechanistic-based combinatorial strategy. DESIGN:We integrated whole-exome sequencing, untargeted metabolomics and single-cell RNA sequencing of human PDAC specimens to analyse the metabolic-immune landscape. We evaluated therapeutic efficacy using the autochthonous mouse and patient-derived xenograft models. RESULTS:We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy. Cotargeting cholesterol metabolism and autophagy potentiated the antitumour efficacy of the KRASG12D inhibitor MRTX1133 and alleviated CD8+ T cell exhaustion. Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival. Genetic depletion or pharmacological inhibition of USP20 with GSK2643943A suppressed these pathways and restored CD8+ T cell function, improving responses to MRTX1133 and anti-programmed cell death protein-1 (anti-PD-1). In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression. CONCLUSION:USP20 acts as a critical metabolic checkpoint that orchestrates CD8+ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRASG12D inhibitors in PDAC.

Proteins identified in RNA pulldown and mass spectrometry analysis with FZR1[m6A] or FZR1[A].

Cancer-associated fibroblasts (CAFs) play a key role in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). However, the potential mechanisms by which CAFs promote chemotherapy resistance have not yet been explored. In this study, we found that circABCC4 (hsa_circ_0030582) was positively correlated with poor platinum-chemotherapeutic response and a shorter progression-free survival (PFS) time in late-stage PDAC patients. CircABCC4 enhanced the ability of CAFs to induce oxaliplatin resistance in pancreatic cancer cells through glycolysis reprogramming. Mechanistically, circABCC4 enhanced the interaction between PKM2 and KPNA2 to promote PKM2 nuclear translocation in CAFs, leading to the transcription of glycolysis-related genes. The glycolytic reprogramming of CAFs promoted the secretion of IL-8, which in turn enhanced DNA damage repair in pancreatic cancer. Blocking PKM2 nuclear translocation abolished circABCC4-driven oxaliplatin resistance of pancreatic cancer in vivo. Collectively, our study reveals a circRNA-mediated glycolysis reprogramming of CAFs to induce oxaliplatin resistance and highlights circABCC4 as a potential therapeutic target.

BACKGROUND:Pancreatic cancer is a highly aggressive malignancy characterized by limited treatment options, poor prognosis, and high mortality rates. nuclear activating miRNA (NamiRNA) enhances gene expression by interacting with nuclear enhancers, offering a novel avenue for understanding gene regulation in cancer. This study explores the dual role of mir-200c in regulating tumor proliferation and migration in pancreatic cancer, with the aim of identifying potential therapeutic strategies. RESULTS:Mir-200c significantly activated PTPN6 transcription via the NamiRNA-enhancer pathway, reducing tumor proliferation. Deletion of the enhancer sequence abolished the activation of PTPN6. Furthermore, mir-200c mediated the post-transcriptional repression of CDH17, impairing tumor migration. In vivo, LNP-enclosed mir-200c exhibited strong anti-tumor effects, further validating its therapeutic potential. CONCLUSIONS:Mir-200c inhibits pancreatic cancer cell proliferation and migration through dual mechanisms: activation of PTPN6 transcription and repression of CDH17 expression. These findings suggest that mir-200c, particularly when delivered via LNP systems, may serve as a promising therapeutic strategy for pancreatic cancer.

BACKGROUND:The survival rate of pancreatic cancer is low, and there is a lack of effective treatment. AIM:To explore the epidemiological characteristics of patients with pancreatic cancer in China and compare multiple chemotherapy regimens at different stages. METHODS:This was a retrospective study conducted from 2005 to 2014, involving six cancer hospitals and eight general hospitals across seven geographical regions of China (East, South, North, Central, Southwest, Northwest, and Northeast). Stratified sampling was used based on the population distribution of each region. Efficacy assessments were conducted by Cox proportional hazards regression models. When assessing the effectiveness of various chemotherapy regimens, traditional drugs such as gemcitabine used as monotherapy served as the reference. RESULTS:A total of 3256 patients were included. The median follow-up time was 407 days, and the median overall survival was 183 days. At diagnosis, 56% of patients were already in stage IV. Chemotherapy was administered to 39.73% of patients. In the adjuvant therapy phase, gemcitabine + fluorouracil was superior to gemcitabine monotherapy [hazard ratio (HR) = 0.35, 95% confidence interval (CI): 0.14-0.89]. In fluorouracil-based regimens, other combination regimens did not show effectiveness relative to monotherapy. For first-line treatment in patients with advanced disease, tegafur alone (HR = 0.20, 95%CI: 0.06-0.66), gemcitabine plus cisplatin (HR = 0.16, 95%CI: 0.04-0.70), and tegafur, gemcitabine plus platinum-based agents (HR = 0.32, 95%CI: 0.11-0.91) were associated with a lower risk of death compared to gemcitabine alone. In second-line treatment, there were no significant differences in efficacy among various drugs, but FOLFIRINOX (irinotecan + oxaliplatin + leucovorin + 5-fluorouracil) had an outstanding point estimate (HR = 0.10, 95%CI: 0.01-1.27). CONCLUSION:In China, pancreatic cancer is often diagnosed at advanced stages, emphasizing the need for early diagnosis and treatment. Combined therapies in adjuvant and first-line settings may reduce the risk of death compared with monotherapy, and FOLFIRINOX might offer more significant benefits in second-line treatment.

Laparoscopic pancreaticoduodenectomy (LPD) has become a widely adopted surgical approach for treating pancreatic head cancer. Traditional open pancreaticoduodenectomy (OPD) is associated with significant surgical trauma, with postoperative hospital stays often exceeding 2 weeks. In contrast, LPD presents higher surgical risks due to the lack of standardized protocols, particularly posing challenges in minimally invasive resection and anastomosis. In addition, the optimal extent of lymphatic and neural dissection in pancreatic head cancer remains controversial and continues to be actively debated. To address these challenges in traditional pancreatic cancer treatment, we developed a modular surgical approach and a dual-surgeon model to systematize laparoscopic pancreatic surgery. Our novel Laparoscopic Programmatic Neurolymphatic Radical Pancreaticoduodenectomy (LPNRPD) technique not only ensures surgical safety but is also user-friendly, making it particularly suitable for laparoscopic surgery beginners. For radical resection of pancreatic head cancer, we propose that complete dissection of the peripancreatic neural plexus is critical for achieving R0 resection. Through multicenter RCT studies, we established standardized protocols for radical neurolymphatic dissection tailored to different subtypes of pancreatic cancer. For patients with resectable pancreatic head cancer (preoperative CA19-9 < 200 U/mL, no vascular invasion), we recommend the LPNRPD strategy. However, the successful implementation of LPNRPD heavily relies on the surgeon's skill and expertise. This article provides a comprehensive overview of the techniques for performing LPNRPD, emphasizing its safety, reproducibility, and applicability in the context of pancreatic head cancer treatment.