e16370 Background: The optimal treatment strategy for patients with synchronous pancreatic ductal adenocarcinoma with liver metastases (sPDACLM) remains uncertain, and the role of surgery in selected patients is controversial. Comparative evidence regarding survival outcomes between upfront surgery (US) and surgery following systemic therapy (SS) in this population is limited. This study aimed to compare overall survival (OS) among patients with sPDACLM treated with different therapeutic strategies and identify prognostic factors associated with survival. Methods: This multicenter retrospective cohort study included patients with sPDACLM treated at seven tertiary medical centers in China between 2017 and 2025. Patients were categorized into three groups: upfront surgery group (US), effective systemic therapy followed by surgery (E-SS), defined as achievement of partial response [PR] per RECIST 1.1 with a > 85% reduction or normalization of serum CA19-9 after systemic therapy; and ineffective systemic therapy followed by surgery (I-SS), defined as fails to achieve PR or < 85% reduction in CA19-9 after systemic therapy. The primary endpoint was OS. Results: A total of 72 patients were included, comprising 21 in the US group, 24 in the E-SS group, and 27 in the I-SS group. Baseline characteristics differed substantially among groups, with 21 of 24 covariates demonstrating a standardized mean difference (SMD) > 0.1. Kaplan–Meier analysis showed significantly improved survival in the E-SS group compared with the US group (median OS: 31.9 vs. 8.0 months; 1-year OS: 90.47% vs. 33.33%; 3-year OS: 40.50% vs. 15.23%) and the I-SS group (median OS: 17.0 months; 1-year OS: 66.62%; 3-year OS: 0%) (P < 0.0001). Univariate Cox regression identified effective systemic therapy as a favorable prognostic factor for OS (hazard ratio [HR], 0.265; 95% CI, 0.123–0.571; P < 0.001). After adjustment for clinically relevant covariates, multivariable Cox analysis confirmed that effective systemic therapy (adjusted HR [aHR] = 0.225, 95% CI: 0.099–0.512; P < 0.001) and tumors located in the pancreatic body–tail region (aHR = 0.443, 95% CI: 0.222–0.882; P = 0.03) were independently associated with prolonged OS. Sensitivity analyses yielded consistent results, supporting the robustness of the findings. Conclusions: Among patients with sPDACLM, treatment strategies incorporating systemic therapy are associated with improved survival compared with upfront surgery. Moreover, tumors arising in the pancreatic body–tail region represent an independent favorable prognostic factor. These findings support prioritizing systemic therapy in the management of sPDACLM, with subsequent surgical resection following systemic therapy offering a clinically meaningful survival benefit.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is usually diagnosed at a late stage and has a modest clinical response and poor prognosis. Therefore, identifying targets for the effective treatment of PDAC is particularly important. STAM-binding protein (STAMBP) is a JAMM metalloprotease of the deubiquitinase (DUB) family that typically regulates the stabilization and trafficking of substrates in a range of cell types by specifically removing ubiquitin chains. However, its roles in the initiation and progression of PDAC remain unclear. Here, we found that STAMBP is highly expressed in PDAC and is associated with a poor prognosis. STAMBP facilitates the proliferation and migration of PDAC cells and the growth of pancreatic cancer xenograft tumours in mice. We then identified the cochaperone BAG3, which plays a pivotal role in tumourigenesis, as a potential substrate of STAMBP using mass spectrometry (MS). Mechanistically, STAMBP interacts with BAG3 and promotes its stabilization by removing its K63-linked polyubiquitin chains. The Lys29 and Lys60 residues of BAG3 are essential for the K63-linked ubiquitination of BAG3. Moreover, a phosphorylation-dependent mechanism of STAMBP was identified as follows: STAMBP is phosphorylated by IKKα at Ser2 without affecting STAMBP protein abundance, and this phosphorylation enables it to deubiquitinate BAG3. In addition, we found that STAMBP deficiency effectively increases cisplatin/oxaliplatin sensitivity in PDAC. Overall, IKKα phosphorylates STAMBP at Ser 2, which activates STAMBP to deubiquitinase BAG3, thus resulting in an IKKα/STAMBP/BAG3 signaling axis that promotes PDAC progression. STAMBP might serve as a potential therapeutic target for PDAC therapy.

Introduction Pancreaticoduodenectomy (PD) is the preferred surgical approach for resectable periampullary carcinomas. Non-pancreatic periampullary carcinomas (NPPC) demonstrate distinct biological behaviours and are generally less aggressive than pancreatic cancer. Despite over three decades of advancements, the role of laparoscopic PD (LPD) remains debated. Few studies have directly compared LPD and open PD (OPD) while accounting for tumour invasiveness, and the data specifically evaluating LPD vs OPD for NPPC are limited. Randomised controlled trials are necessary to determine whether therapeutic outcomes differ between LPD and OPD in NPPC patients.Methods and analysis The TJDBPS14 trial is a prospective, randomised controlled, open-label, multicentre non-inferiority study with a parallel-group design. All participating surgeons have performed at least 104 LPD and OPD procedures. A total of 212 selected patients diagnosed with NPPC and eligible for PD will be randomly assigned to either LPD or OPD. The primary outcome is postoperative hospital stay, with secondary outcomes including 1-year survival rate, perioperative outcomes, incidence of perioperative complications, short-term outcomes and quality of life. The hypothesis is that the postoperative hospital stay for the LPD group will not exceed that of the OPD group.Ethics and dissemination This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, with independent third-party monitoring. The results of the trial will be presented at international conferences and published in peer-reviewed journals.Trial registration number NCT05788029. Registered on 30 November 2022.

The detection of single-base mutation in ctDNA with liquid biopsy is of great significance for the early diagnosis of pancreatic cancer. CRISPR-Cas system has attracted widespread attention in liquid biopsy due to its robust nuclease activity, extremely strong signal amplification capability and higher sensitivity. However, there is still a lack of a CRISPR-Cas-based method for single-base mutation detection that possesses high sensitivity and specificity while being simple to operate and highly practical. In this study, we innovatively designed a Double Blocker Integrated CRISPR-Cas14a (DBIC) system by introducing blocking RNA and blocking DNA. Our system can greatly improve the discrimination efficiency for base mismatches. Both theoretical analysis and experimental verification have confirmed that the limit of detection of this method can be as low as 0.0005%, which fully meets the requirements for early cancer screening. In the detection of actual clinical samples, we successfully achieved the identification of three highly prevalent hotspot mutation sites of pancreatic cancer using the DBIC system, and its effectiveness was verified by comparison with the results of NGS. Featuring simple operation, low cost and ultra-low detection limit, our system holds great promise for widespread clinical application.

e16403 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) liver metastases have a poor prognosis, and the best treatment remains uncertain. While systemic chemotherapy is standard, the benefit of liver metastasis resection in oligometastatic patients lacks high-level evidence, with many studies affected by bias and mixed results. This study evaluates the effect of synchronous liver metastasis resection on overall survival, adjusted for confounders through multicentre, propensity score-matched analysis, and identifies independent prognostic factors. Methods: This retrospective multicenter study in seven Chinese centers enrolled patients with pancreatic cancer and liver metastases from January 2017 to July 2025. Patients were divided into complete liver lesion management and partial/untreated groups based on intervention extent. Propensity score matching used covariates like sex, tumor location, and metastasis burden, with oligometastasis defined as < 3 lesions without extrahepatic spread. The primary endpoint was overall survival. Kaplan- Meier and Cox regression analysis compared groups and identified prognostic factors. Results: After matching, 48 patients (24 in each group) formed a balanced cohort. No significant baseline differences were found. Median survival was 19 months in the complete management group and 25 months in the partial/untreated group, with no significant difference (HR = 1.07. 07, P = 0. 853). Univariate analysis showed preoperative neoadjuvant chemotherapy, higher BMI, and lower ALT levels were associated with better prognosis. Multivariate analysis confirmed preoperative neoadjuvant chemotherapy and higher BMI as independent favorable factors. Subgroup analysis indicated complete metastasis management did not improve survival among those responding to neoadjuvant chemotherapy. Conclusions: This study found that aggressive liver metastasis resection does not significantly prolong survival. Systemic therapy, especially neoadjuvant chemotherapy, and nutritional status (BMI) are stronger prognostic factors. The results suggest focus should be on systemic and health management rather than aggressive surgery, providing high- level evidence supporting' chemotherapy over surgery" in this setting.

Cancer cells undergo metabolic reprogramming to meet the demands of rapid proliferation, survival and chemotherapy resistance. Targeting cancer-specific metabolic vulnerabilities offers a compelling strategy for therapeutic intervention. Owing to the Warburg effect and the unique tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells exhibit a high demand for glucose to sustain their energy metabolism. Here, we identify a novel regulatory mechanism controlling the cell surface abundance of glucose transporter 1 (GLUT1), mediated by RAB8A-dependent vesicular trafficking. RAB8A, a member of the RAS oncogene family, enhances GLUT1 membrane localization and thereby increases glucose uptake in PDAC cells. Mechanistically, we demonstrate that ubiquitin-specific peptidase 20 (USP20) negatively regulates RAB8A activation by selectively removing K48-linked polyubiquitin chains from its inactive form. Functional assays in vitro and in vivo validate the tumor-suppressive role of the USP20-RAB8A signaling axis. Furthermore, using primary PDAC cells derived from KPC (KrasG12D/+; Trp53 R172Hflox/flox; Pdx1-Cre) mice, we show that dual knockdown of Rab8a and Glut1 markedly attenuates tumor-promoting effects driven by oncogenic Kras and Trp53 loss. Collectively, our findings reveal that the USP20-RAB8A-GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.

Traditional CRISPR-Cas12a mutation detection systems are limited by poor single-base specificity, target-specific crRNA redesign, and insufficient sensitivity for low-abundance mutations, restricting their clinical liquid biopsy applications. Herein, we developed a crRNA-universal, sensitive and specific CRISPR-Cas12a detection platform, termed DESIC (double-end blocker and split-input mediated CRISPR-Cas12a system), for single-base mutation detection. The DESIC system adopts two key structural designs: double-end blocker (DEB) and duplicated split-input (SIN). The DEB spatially isolates crRNA recognition and target-binding regions, enabling universal detection of various mutation sites without crRNA redesign. The SIN strategy amplifies thermodynamic differences from single-base mismatches, greatly improving single-nucleotide discrimination. We targeted four prevalent pancreatic cancer KRAS mutations (G12D, G12R, G12V, Q61H) and optimized the system to achieve optimal discrimination. The optimized DESIC system exhibited ultra-low limits of detection down to 0.01% mutant allele fraction with reliable linear quantitative performance. Clinical validation using 15 pairs of pancreatic cancer tissue and peripheral blood samples confirmed that DESIC results were highly consistent with gold-standard NGS data. With a flexible modular design, this low-cost, easy-operated platform can be readily extended to multiple tumor mutations, holding great potential for tumor liquid biopsy and early molecular diagnosis.

e16365 Background: The role of surgical intervention in pancreatic ductal adenocarcinoma with synchronous liver metastases (sPDACLM) remains controversial. While systemic therapy is the mainstay, select patients demonstrating significant response may benefit from surgery. This study aimed to identify optimal criteria for selecting patients with sPDACLM for conversion surgery. Methods: This multicenter, retrospective cohort study analyzed patients with sPDACLM from seven Chinese centers (2017-2025). Key inclusion criteria were age ≥18, ECOG 0-1, biopsy-proven PDAC with liver metastases, and completion of ≥4 cycles of first-line systemic therapy. Patients were stratified by primary tumor resectability into an "Intention-to-Conversion Surgery (ITCS)" group (resectable/borderline resectable primary tumor) and a "Maintenance Therapy" group (unresectable primary tumor). Treatment response was assessed radiographically (RECIST 1.1 Partial Response [PR]) and biochemically (CA19-9 decline > 85% or normalization); patients meeting both criteria were classified as "Dual Responder." The primary endpoint was overall survival (OS). Results: Of 175 eligible patients, 135 were in the ITCS group and 40 in the maintenance therapy group. The median OS for the entire cohort was 13 months. The ITCS group had significantly longer median OS than the maintenance therapy group (14.0 vs. 11.4 months, P = 0.015). Multivariate analysis confirmed biochemical response, radiographic response, and baseline neutrophil-to-lymphocyte ratio (NLR) as independent prognostic factors for OS. "Dual responder" (n = 46/175, 26.3%) had a significantly superior median OS of 23.0 months compared to 11.0 months in non-responders (P < 0.001). Within the ITCS group (n = 135), "Dual responder" (n = 46, 34.1%) achieved a median OS of 24.8 months versus 11.0 months in non-responders (P < 0.001). Among these 46 "Dual responder," those who underwent surgery (n = 22) had a significantly longer median OS than those who did not (31.9 vs. 18.0 months, P = 0.05), with a 5-year survival rate of 19%. In contrast, for patients not meeting the dual criteria (n = 89), surgery did not confer a significant long-term OS benefit despite potential short-term improvement. Conclusions: The "Dual response" criteria—combining radiographic partial response (RECIST 1.1 PR) and a major biochemical response (CA19-9 decline > 85% or normalization)—effectively identifies a subgroup of patients with sPDACLM who may derive significant survival benefit from conversion surgery. Surgical intervention is not recommended for patients who fail to meet these dual criteria. These findings provide a practical framework for patient selection in the multimodal management of pancreatic ductal adenocarcinoma with synchronous liver metastases.

Background:Circular RNAs (circRNAs) play a pivotal role in the development and advancement of various cancer types. However, the involvement of circ-PAN3 in hepatocellular carcinoma (HCC) is not well understood. To shed light on this, we conducted a comprehensive study through biochemistry, cell biology, molecular biology, and bioinformatics techniques to investigate the role of circ-PAN3 and its associated pathway in the progression of HCC. Methods:Cell Counting Kit-8 (CCK-8) assay and colony formation assay were utilized to evaluate cell proliferation; Quantitative real-time PCR (RT-qPCR) and Western blot were adopted for assessing mRNA and protein expression; Annexin V/propidium iodide (PI) staining was applied to detect cellular apoptosis; CircInteractome and Targetscan databases were searched to predict potential targets of circRNA and miRNA; Luciferase reporter assay and RNA pull-down assay were performed to examine the interaction of RNA molecules. Conclusions:Our findings revealed a significant increase in circ-PAN3 expression in HCC clinical specimens, which correlated with a poor survival rate in HCC patients. Knockdown of circ-PAN3 resulted in impaired cell proliferation, reduced cell survival, and inhibited tumorigenesis of HCC in vivo. Further analysis demonstrated that circ-PAN3 could serve as a sponge for miR-153, leading to a decrease in its expression level. This in turn upregulated cyclin D1 and ultimately promoted the proliferation of HCC cells. Additionally, overexpression of cyclin D1 mitigated the inhibitory effect on HCC proliferation induced by circ-PAN3 knockdown. Our study highlights the presence of a novel circ-PAN3/miR-153/cyclin D1 regulatory axis that plays a crucial role in the progression of HCC.

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.

Lactylation, a novel post-translational modification identified in 2019, has gained increasing recognition for its critical role in oncogenesis and cancer progression. However, systematic analyses of research trends in this field using bibliometric approaches remain scarce. This study conducted comprehensive bibliometric evaluations of 240 documents from the Web of Science Core Collection SCI-expanded (SCIE) using CiteSpace, VOSviewer, and Scimago Graphica, focusing on authors, institutions, countries, keywords and citations. Key findings indicate that China and the United States are the predominant contributors to this field, with the Chinese Academy of Sciences being identified as the most productive and influential institution. Temporal analysis demonstrates a threefold increase in the number of publications by 2024, highlighting the field’s rapid expansion. Notably, collaboration remains restricted, as over 95% of partnerships occur within China, which underscores the necessity for strengthened international cooperation. Moreover, our analysis confirms that lactylation serves as a critical mechanistic bridge linking lactate metabolic reprogramming to cancer hallmarks, such as immune evasion, angiogenesis, invasion, and metastasis. Through systematic evaluation, we have catalogued thirty-eight non-histone substrates of lactylation implicated in cancer. Overall, this work elucidates the trends and emerging hotspots in cancer-related lactylation research, providing valuable quantitative insights for future investigations.

BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver in individuals who do not consume alcohol. Several risk factors influencing the onset of NAFLD after laparoscopic pancreaticoduodenectomy (LPD) have been identified. This study investigated the risk factors associated with the development of fatty liver after laparoscopic duodenum-preserving pancreatic total head resection (LDPPHRt) and LPD. AIM:To compare the effects of LDPPHRt and LPD on the development of postoperative NAFLD. METHODS:This retrospective cohort study included 59 patients who were histologically diagnosed with benign or low-grade malignant pancreatic tumors and who underwent laparoscopic pancreatic surgery (LDPPHRt or LPD) between May 2020 and April 2023. Patient data on perioperative and postoperative variables were analyzed and compared. Multivariate logistic regression was used to identify pre-, peri-, and postoperative risk factors for NAFLD, with statistical significance set at P < 0.05. RESULTS:Of the 59 patients included in the study, 17 (28.8%) developed NAFLD within 6-12 months post-surgery. The incidence of NAFLD was significantly higher in the LPD group compared to the LDPPHRt group (40.0% vs 12.5%, P = 0.022). Multivariable analysis identified the LDPPHRt surgical approach (compared to LPD) as an independent protective factor against the development of postoperative NAFLD, with an odds ratio of 0.208 (95% confidence interval: 0.046-0.931; P = 0.040). CONCLUSION:Our findings indicate that LDPPHRt is more effective than LPD in reducing the incidence of postoperative NAFLD, which may inform surgical decision-making and optimize patient outcomes after laparoscopic pancreatic surgery.

Pancreatic cancer is a highly aggressive malignancy characterised by its invasive nature and poor therapeutic outcomes. These characteristics are closely associated with its complex biological characteristics and significant heterogeneity. Post-translational modifications (PTMs) have been identified as critical regulatory mechanisms through which cells respond to environmental changes and play a pivotal role in signal transduction. The various types of PTMs and their intricate regulatory mechanisms have a profound influence on multiple stages of pancreatic cancer progression. Research has demonstrated that PTMs modulate protein stability, activity, subcellular localization, and protein–protein interactions. The present review focuses on recent advances in our understanding of PTMs in pancreatic cancer, with a particular emphasis on phosphorylation, ubiquitination, SUMOylation, acetylation, lactylation, and O-GlcNAcylation. This study illuminates the molecular mechanisms and functional regulatory networks of PTMs within the distinctive tumour microenvironment of pancreatic cancer. Moreover, we summarise targeted therapeutic strategies directed at PTMs in pancreatic cancer to provide insights for future research and treatment development.

Early cancer screening for single base mutation is of paramount importance in order to reduce the incidence and mortality of cancer, particularly pancreatic cancer. Liquid biopsy technology represents a pivotal technology in the field of early cancer screening due to its non-invasiveness. The current detection methods include high-throughput sequencing and nucleic acid probe detection. These methods still can’t combine low detection limits, versatility and low cost. In this study, we developed the T-shaped probe detection system. The system exploits the design of the T-shaped structure, taking into account the signal amplification advantage of endonuclease IV and the high discrimination of the four-strand-displacement reaction for single-base mutations. The feasibility of the reaction principle was demonstrated at both the theoretical and experimental levels. On this basis, we have developed a multiple platform for sequential mutation detection by incorporating C and C' into the reaction system. Finally, we verified that the reaction platform is capable of sequential detection of PCR products from clinical samples with abundance as low as 0.02%. It is our contention that this detection system, when combined with integrated, microchip-based processing, has the great potential to be applied to clinical bedside diagnostics in the future.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide. Our research endeavored to delineate the role of circPTEN and to assess its potential as a prognostic biomarker in HCC. CircPTEN expression was quantified in HCC cells and clinical specimens using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of circPTEN overexpression on cellular activities were evaluated through Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EDU), and Transwell assays. The impact of circPTEN overexpression on HCC tumorigenesis and metastasis was also assessed in xenograft mouse models. Kaplan-Meier survival analysis was conducted to assess circPTEN's prognostic value, while additional experiments were conducted to examine the circPTEN-microRNA-1289 (miR-1289) interaction and Eukaryotic Initiation Factor 4A3 (EIF4A3) regulatory effect on circPTEN expression. Our investigations revealed significantly reduced circPTEN expression in HCC, with lower levels correlating with poorer patient outcomes. In vitro experiments demonstrated that enhancing circPTEN expression could inhibit both the proliferation and invasiveness of HCC cells. At the molecular level, circPTEN functioned as a microRNA sponge for miR-1289, consequently upregulating RNA Binding Motif Protein 38 (RBM38), a validated tumor suppressor in HCC. Furthermore, EIF4A3 was identified as a negative regulator of circPTEN expression in HCC cells. Nude mouse model experiments corroborated our in vitro results, showing that increased circPTEN expression corresponded with reduced tumorigenesis and metastatic spread. CircPTEN functions as a tumor suppressor in HCC, regulating the miR-1289/RBM38 axis while being negatively regulated by EIF4A3. Restoration of circPTEN expression represents a potential therapeutic strategy for HCC, and circPTEN levels may serve as a candidate prognostic biomarker.

Gallbladder cancer (GBC) remains a challenging malignancy with a poor prognosis largely due to its highly metastatic nature and lack of effective treatment options. In this study, we investigated the role of N6-methyladenosine (m6A) modification and its regulatory factors, METTL3 and METTL14, in GBC. Our results showed that m6A levels as well as the expression of METTL3 and METTL14 were significantly downregulated in GBC tissues compared to normal gallbladder tissues. In vitro experiments showed that manipulation of METTL3 and METTL14 expression regulated GBC cell migration and invasive ability, and the liver metastasis model of nude mice further demonstrated the involvement of m6A modification in regulating GBC metastasis. Further investigation identified miR-146a-5p as a downstream target regulated by m6A, with tumour-suppressive effects on GBC cell migration and invasion. Overall, our findings provide new insights into the role of m6A modification and its regulation on microRNA in GBC pathogenesis and offer a potential strategy for the treatment of GBC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal gastrointestinal cancers worldwide. The diagnostic and treatment limitations have resulted in great challenges in improving the survival of patients with PDAC. Ubiquitination is an indispensable posttranslational modification involved in all cellular processes via proteolytic or nonproteolytic pathways. Deubiquitinating enzymes (DUBs) comprise ~100 proteases that remove ubiquitin from targeted proteins to regulate cellular physiological or pathological processes. Accumulating evidence has shown that DUBs are involved in the regulation of the occurrence and development of cancers. Currently, a substantial number of studies have reported that DUBs are involved in the malignant progression of PDAC. Hence, we summarize and review the latest research advances in understanding the mechanism by which DUBs are involved in modulating the development of PDAC, including proliferation, migration, invasion, metastasis, metabolic reprogramming, and chemoresistance. In addition, we present studies on how DUBs affect the immune microenvironment of PDAC and briefly characterize some therapeutic perspectives of PDAC that ultimately depend on the targeting of DUBs.

Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis1. Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR-PTPN11-FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

Objective: To compare the perioperative outcomes of laparoscopic duodenal-preserving pancreatic head resection(LDPPHR) with laparoscopic pancreaticoduodenectomy(LPD) in the treatment of borderline and benign diseases of the pancreatic head. Methods: This is a retrospective cohort study. Perioperative data from 87 patients with non-malignant pancreatic head diseases who underwent LDPPHR or LPD were retrospectively collected in the Department of Biliary-Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2020 to December 2022. There were 49 male and 38 female patients with an age (M(IQR)) of 57.0(16.5) years (range: 20 to 75 years). Forty patients underwent LDPPHR and 47 patients underwent LPD. Quantitative data following a normal distribution were compared using Student's t-test, while quantitative data not following a normal distribution were compared using the Mann-Whitney U test. Comparisons of categorical or ordinal variables were made using χ2 test or Fisher's exact test. Logistic regression analysis was used to estimate the risk factors associated with the rate of complications. Results: There were no statistically significant differences between the LDPPHR group and the LPD group in terms of reoperation rate,total hospital stay duration,postoperative hospital stay duration,90-day mortality rate,30-day and 90-day readmission rates,and 2-year tumor recurrence rate (all P>0.05). The complication rate was higher in the LDPPHR group compared to the LPD group (80.0%(32/40) vs. 51.1%(24/47), χ2=7.89,P=0.005),but there was no difference in the rate of Clavien-Dindo classification of surgical complications ≥Ⅲ between the two groups (10.0%(4/40) vs. 12.8%(6/47), χ2<0.01, P=0.947). Additionally,the rate of delayed gastric emptying (DGE) was higher in the LDPPHR group compared to the LPD group (χ2=10.79,P=0.001),but there was no statistically significant difference in the rate of B,C grade DGE between the two groups (χ2=0.48, P=0.487). There were no statistically significant differences in the rates of postoperative pancreatic fistula,bile leakage,post-pancreatectomy hemorrhage,intra-abdominal infection,and pulmonary infection between the two groups (all P>0.05). The results of the univariate logistic regression analysis showed that LDPPHR (compared to LPD, OR=3.83, 95%CI: 1.46 to 10.04, Z=2.73,P=0.006) and preoperative biliary stent placement (compared to non-use of biliary stent, OR=5.30, 95%CI: 1.13 to 25.00, Z=2.11, P=0.035) were risk factors for the complication rate,but neither was an independent risk factor for complication rate (all P>0.05). Conclusion: The preliminary results suggest that LDPPHR can achieve perioperative safety and effectiveness comparable to LPD.