Search Results (43)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and approximately 15% of cases arise from intraductal papillary mucinous neoplasms (IPMNs). These precursor lesions can progress to invasive cancer through the accumulation of molecular alterations. To identify pathways associated with this transition, we performed comparative transcriptomic analyses of patient-derived IPMN and PDAC samples, followed by protein-level validation in tissue specimens and pancreatic cancer cell lines. Functional studies were conducted using the selective p38α inhibitor ralimetinib in two-dimensional cultures, three-dimensional tumorspheres, and patient-derived tumor organoids (PDTOs). Transcriptomic profiling revealed significant downregulation of the p38 pathway in IPMNs compared with PDAC, suggesting progressive pathway activation during pancreatic tumorigenesis. Immunohistochemical analyses confirmed increased phospho-activated p38α in PDAC tissues, particularly in lesions with advanced malignant features, while PDAC cell lines displayed higher levels of activated p38α than non-tumorigenic pancreatic epithelial cells. Pharmacological inhibition of p38α suppressed downstream MAPKAPK2 phosphorylation, induced apoptotic cell death, and reduced tumorsphere growth and viability. Consistently, PDTOs exhibiting elevated p38α activation showed increased sensitivity to ralimetinib treatment. Collectively, these findings identify p38α signaling as a pathway activated during PDAC progression and support further investigation of p38α-targeted therapies as a potential precision medicine strategy for pancreatic cancer. Full article

Background/Objectives: Annexin A4 (ANXA4) is one of twelve members of the annexin superfamily that bind membrane phospholipids in a calcium-dependent manner, and which are involved in several processes related to the membrane. Methods: To learn more about the role of ANXA4 in cancer, the ANXA4 expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMAs) containing 17,654 tumors and precursor lesions from 148 tumor types. Results: ANXA4 immunostaining was found in 10,858 (83.4%) of 13,017 analyzable tumors, and was considered weak in 10.1%, moderate in 16.6%, and strong in 61.8% of cases. Of 148 tumor categories, 144 showed ANXA4 staining in at least one case and 133 included at least one case with strong staining. Among tumor entities with at least 10 evaluable samples, strong ANXA4 staining in >50.0% of cases was seen in 56 of 120 entities, while absence of staining in >50.0% of cases was seen in 13. Clinically important tumor entities where ANXA4 staining was always positive (>99.5%) included gallbladder adenocarcinoma, cholangiocarcinoma, pancreatic/ampullary, various subtypes of salivary gland tumors, papillary renal cell carcinoma, urothelial carcinoma, squamous and basal cell carcinoma of the skin, and epithelioid mesothelioma. A reduced ANXA4 expression was linked to features of cancer aggressiveness in breast cancer, clear cell renal cell carcinoma, urothelial carcinoma, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, colorectal adenocarcinoma, and follicular thyroid carcinoma. Conclusions: It is concluded that ANXA4 is abundantly expressed in human malignancies and that a reduced expression may be linked to unfavorable disease characteristics in many important tumor entities. Full article

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer. This study investigated the association between MRI-derived pancreatic fat fraction and IPMN. Materials and Methods: This retrospective case–control study included 60 patients with IPMN and 120 controls evaluated between 2018 and 2025. All participants underwent pancreatic MRI with proton density fat fraction (PDFF) imaging. Pancreatic fat fraction was measured in the pancreatic head, body, and tail on PDFF maps, and mean pancreatic fat fraction was calculated. Group comparisons, receiver operating characteristic analysis, and logistic regression analyses were performed to evaluate the association between pancreatic fat fraction and IPMN. Results: A total of 180 participants were included in the study, comprising 60 patients with IPMN and 120 controls without IPMN. Patients with IPMN were significantly older than controls (72.5 vs. 57.0 years, p = 0.001). The IPMN group demonstrated higher glucose and LDH levels and lower HDL cholesterol, hemoglobin, hematocrit, and platelet counts compared with controls (all p < 0.05). Pancreatic fat fraction measurements were significantly increased in patients with IPMN across all pancreatic regions. Head, body, tail, and mean pancreatic fat fractions were markedly higher in the IPMN group than in controls (all p = 0.001). In multivariable logistic regression analyses, age and pancreatic fat fraction remained independently associated with IPMN presence. ROC analysis demonstrated excellent diagnostic performance, with mean pancreatic fat fraction showing the highest discriminative ability (AUC = 0.968), followed by head (AUC = 0.934), body (AUC = 0.922), and tail fat fraction (AUC = 0.876). Conclusions: Pancreatic fat fraction was significantly higher in patients with IPMN and remained independently associated with IPMN presence after multivariable adjustment. Mean pancreatic fat fraction demonstrated excellent diagnostic performance for distinguishing IPMN from non-IPMN individuals. Quantitative MRI-based assessment of pancreatic fat may represent a useful imaging biomarker for IPMN detection. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy. The identification and management of precursor lesions, particularly the increasingly common intraductal papillary mucinous neoplasms (IPMNs), pose a significant challenge, creating a profound clinical dilemma between intercepting pancreatic ductal adenocarcinoma and avoiding surgical overtreatment. This literature review aims to synthesize the latest evidence to facilitate a transition from purely morphology-based surveillance toward a biologically informed risk stratification paradigm. This approach could provide a personalized risk-stratification algorithm that optimizes therapeutic management and enables timely intervention for pancreatic cancer. By using PubMed, Embase, Scopus, and Web of Science, we analyzed and summarized key findings from recent literature (2020–2025), including cohort studies, mechanistic analyses, evidence-based guidelines, and systematic reviews on cyst fluid biomarkers (CEA panels, DNA/RNA sequencing), and emerging AI applications. Prospective and multicenter studies consistently report that NOD is independently associated with high-risk stigmata, cyst progression, and malignant transformation. Mechanistic research suggests a bidirectional interplay between the evolving neoplasia and pancreatic endocrine dysfunction. Updated guidelines underscore the need for more precise diagnostic algorithms. Recent work demonstrates that advanced cyst fluid markers—CEA panels, DNA/RNA sequencing, and multi-omic signatures—significantly improve diagnostic accuracy. Furthermore, explainable AI models show encouraging performance in predicting malignancy and assisting patient triage. Risk stratification in PCLs is shifting from morphology-based assessment toward integrated, multimodal approaches combining clinical, endocrine, imaging, molecular, and computational data. Recent evidence positions new-onset diabetes as a clinically accessible and biologically plausible marker of high-risk IPMNs. Similarly, molecular assays and AI-enhanced analytics provide an additional layer of diagnostic precision. The development of personalized risk prediction algorithms could improve early detection of malignancy while reducing unnecessary surgical resections. Full article

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that frequently presents at an advanced stage with limited effective treatment options and a dismal prognosis. It is a highly heterogenous disease driven by various genetic and epigenetic alterations. Recent advances in sequencing modalities have significantly improved our understanding of the genetics of PDAC, which could lead to promising and novel therapeutic strategies. In this review, we summarize the most up-to-date literature on the molecular landscape of PDAC and its precursor lesions, as well as recent advances in targeted therapy. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal malignancies, with a five-year survival rate below 12%, largely attributable to its asymptomatic onset, late-stage diagnosis, and limited curative treatment options. Although PDAC accounts for approximately 3% of all cancers, it is projected to become the second leading cause of cancer-related mortality in the United States by 2030. A major contributor to its dismal prognosis is the lack of validated early detection strategies for asymptomatic individuals. In this review, we present a comprehensive synthesis of current advances in the early detection of PDAC, with a focus on the identification of high-risk populations, novel biomarker platforms, advanced imaging modalities, and artificial intelligence (AI)-driven tools. We highlight high-risk groups—such as those with new-onset diabetes after age 50, pancreatic steatosis, chronic pancreatitis, cystic precursor lesions, and hereditary cancer syndromes—as priority populations for targeted surveillance. Novel biomarker panels, including circulating tumor DNA (ctDNA), miRNAs, and exosomes, have demonstrated improved diagnostic accuracy in early-stage disease. Recent developments in imaging, such as multiparametric MRI, contrast-enhanced endoscopic ultrasound, and molecular imaging, offer improved sensitivity in detecting small or precursor lesions. AI-enhanced radiomics and machine learning models applied to prediagnostic CT scans and electronic health records are emerging as valuable tools for risk prediction prior to clinical presentation. We further refine the Define–Enrich–Find (DEF) framework to propose a clinically actionable strategy that integrates these innovations. Collectively, these advances pave the way for personalized, multimodal surveillance strategies with the potential to improve outcomes in this historically challenging malignancy. Full article

Pancreatic cancer (PC) is highly aggressive, with a 5-year survival rate of 12.8%, making early detection vital. However, non-specific symptoms and precursor lesions complicate diagnosis. Existing tools for the early detection of PC are limited. CAFs are crucial in cancer progression, invasion, and metastasis, yet their role in PC is poorly understood. This study analyzes mRNA data from PC samples to identify CAF-related genes and drugs for PC treatment using algorithms like EPIC, xCell, MCP-counter, and TIDE to quantify CAF infiltration. Weighted gene co-expression network analysis (WGCNA) identified 26 hub genes. Our analyses revealed eight prognostic genes, leading to establishing a six-gene model for assessing prognosis. Correlation analysis showed that the CAF risk score correlates with CAF infiltration and related markers. We also identified six potential drugs, observing significant differences between high-CAF and low-CAF risk groups. High CAF risk scores were associated with lower responses to immunotherapy and higher tumor mutation burdens. GSEA indicated that these scores are enriched in tumor microenvironment pathways. In summary, these six model genes can predict overall survival and responses to chemotherapy and immunotherapy for pancreatic cancer, offering valuable insights for future clinical strategies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar–ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes. Full article

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with a 5-year survival rate of only 12.8%, and its increasing incidence in Western countries highlights the urgent need for better early-stage detection and treatment methods. Early diagnosis significantly improves the chances of survival, but non-specific symptoms and undetectable precursor lesions pose a major challenge. To date, there are no reliable screening tools to detect PDAC at an early stage. Herpesvirus entry mediator (HVEM) has already been proposed as a prognostic marker in numerous cancer types. Therefore, we investigated the role of HVEM in PDAC. Flow cytometry was used to analyze HVEM expression in immune cells and its inhibitory receptors (CD160 and BTLA) on T-cells, as well as its subsets in the peripheral blood of 57 diagnosed PDAC patients and 17 clinical controls. In addition, survival analyses were performed within the PDAC cohort, changes in HVEM expression were analyzed in relation to clinicopathological parameters, and a correlation analysis between HVEM expression and cytokine levels of IL-6 and IL-10 was conducted. Furthermore, HVEM expression on monocytes and their subsets was evaluated as a potential prognostic marker and compared with the prognostic utility of CA19-9. We found that HVEM expression is significantly elevated on immune cells, particularly on monocytes (p < 0.0001) and their subsets, in PDAC patients, and is associated with reduced survival (p = 0.0067) and clinicopathological features such as perineural, lymphovascular, and vascular invasion. Moreover, HVEM-expressing monocytes demonstrated superior predictive value compared to CA19-9, highlighting their potential as part of a combined screening tool for PDAC. In conclusion, HVEM on monocytes could serve as a novel prognostic marker for PDAC. Full article

Pancreatic cystic lesions (PCLs) represent a spectrum of non-neoplasms and neoplasms with varying malignant potential, posing significant challenges in diagnosis and management. While some PCLs are precursors to pancreatic cancer, others remain benign, necessitating accurate differentiation for optimal patient care. Conventional approaches to PCL management rely heavily on radiographic imaging, and endoscopic ultrasound (EUS) guided fine-needle aspiration (FNA), coupled with clinical and biochemical data. However, the observer-dependent nature of image interpretation and the complex morphology of PCLs can lead to diagnostic uncertainty and variability in patient management strategies. This review critically evaluates current PCL diagnosis and surveillance practices, showing features of the different lesions and highlighting the potential limitations of conventional methods. We then explore the potential of artificial intelligence (AI) to transform PCL management. AI-driven strategies, including deep learning algorithms for automated pancreas and lesion segmentation, and radiomics for analyzing heterogeneity, can improve diagnostic accuracy and risk stratification. These advanced techniques can provide more objective and reproducible assessments, aiding clinicians in decision-making regarding follow-up intervals and surgical interventions. Early results suggest that AI-driven methods can significantly improve patient outcomes by enabling earlier detection of high-risk lesions and reducing unnecessary procedures for benign cysts. Finally, this review emphasizes that AI-driven approaches could potentially reshape the landscape of PCL management, ultimately leading to improved pancreatic cancer prevention. Full article

Background: Oncogenic mutations in the KRAS gene are detected in >90% of pancreatic cancers (PC). In genetically engineered mouse models of PC, oncogenic KRAS drives the formation of precursor lesions and their progression to invasive PC. The Yes-associated Protein (YAP) is a transcriptional coactivator required for transformation by the RAS oncogenes and the development of PC. In Ras-driven tumors, YAP can also substitute for oncogenic KRAS to drive tumor survival after the repression of the oncogene. Ras oncoproteins exert their transforming properties through their downstream effectors, including the PI3K kinase, Rac1 GTPase, and MAPK pathways. Methods: To identify Ras effectors that regulate YAP, YAP levels were measured in PC cells exposed to inhibitors of oncogenic K-Ras and its effectors. Results: In PC cells, the inhibition of Rac1 leads to a time-dependent decline in YAP protein, which could be blocked by proteosome inhibitor MG132. This YAP degradation after Rac1 inhibition was observed in a range of cell lines using different Rac1 inhibitors, Rac1 siRNA, or expression of dominant negative Rac1^T17N mutant. Several E3 ubiquitin ligases, including SCF^βTrCP, regulate YAP protein stability. To be recognized by this ligase, the βTrCP degron of YAP (amino acid 383–388) requires its phosphorylation by casein kinase 1 at Ser384 and Ser387, but these events must first be primed by the phosphorylation of Ser381 by LATS1/2. Using Flag-tagged mutants of YAP, we show that YAP degradation after Rac1 inhibition requires the integrity of this degron and is blocked by the silencing of βTrCP1/2 and by the inhibition of casein kinase 1. Unexpectedly, YAP degradation after Rac1 inhibition was still observed after the silencing of LATS1/2 or in cells carrying a LATS1/2 double knockout. Conclusions: These results reveal Rac1 as an oncogenic KRAS effector that contributes to YAP stabilization in PC cells. They also show that this regulation of YAP by Rac1 requires the SCF^βTrCP ligase but occurs independently of the LATS1/2 kinases. Full article

Pancreatic cancer is a rare but lethal cancer due to its biologically aggressive nature, advanced stage at the time of diagnosis, and poor response to oncologic therapies. The risk of pancreatic cancer is significantly higher to 5% in certain high-risk individuals with inherited genetic susceptibility. Screening for pancreatic cancer in these individuals from high-risk groups can help with the early detection of pancreatic cancer as well as the detection of precursor lesions leading to early surgical resection and improved overall outcomes. The advancements in radiological imaging as well as advanced endoscopic procedures has made a significant impact on the early diagnosis, surveillance, and staging of pancreatic cancer. There is also a significant advancement in the development of biomarkers for the early detection of pancreatic cancer, which has also led to the development of liquid biopsy, allowing for microRNA detection in serum and circulating tumor cells. Various societies and organizations have provided guidelines for pancreatic cancer screening and surveillance in high-risk individuals. In this review, we aim to discuss the hereditary risk factors for developing pancreatic cancer, summarize the screening recommendations by different societies, and discuss the development of novel biomarkers and areas for future research in pancreatic cancer screening for high-risk individuals. Full article

Pancreatic cancer is on track to become the second leading cause of cancer-related deaths by 2030, yet there is a lack of accurate diagnostic tests for early detection. Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer and are increasingly being detected. Despite the development and refinement of multiple guidelines, diagnosing high-grade dysplasia or cancer in IPMNs using clinical, radiologic, endosonographic, and cyst fluid features still falls short in terms of accuracy, leading to both under- and overtreatment. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a novel technology that allows real-time optical biopsies of pancreatic cystic lesions. Emerging data has demonstrated that EUS-nCLE can diagnose and risk stratify IPMNs more accurately than conventional diagnostic tools. Implementing EUS-nCLE in clinical practice can potentially improve early diagnosis of pancreatic cancer, reduce unnecessary surgeries of IPMNs with low-grade dysplasia, and advance the field of digital pathomics. In this review, we summarize the current evidence that supports using EUS-nCLE as a diagnostic imaging biomarker for diagnosing IPMNs and for risk stratifying their degree of neoplasia. Moreover, we will present emerging data on the role of adding artificial intelligence (AI) algorithms to nCLE and integrating novel fluid biomarkers into nCLE. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8⁺ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8⁺ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8⁺ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA. Full article

Pancreatic cystic disease, including duct dilation, represents precursor states towards the development of pancreatic cancer, a form of malignancy with relatively low incidence but high mortality. While most of these cysts (>85%) are benign, the remainder can progress over time, leading to malignant transformation, invasion, and metastasis. Cytologic diagnosis is challenging, limited by the paucity or complete absence of cells representative of cystic lesions and fibrosis. Molecular analysis of fluids collected from endoscopic-guided fine-needle aspiration of pancreatic cysts and dilated duct lesions can be used to evaluate the risk of progression to malignancy. The basis for the enhanced diagnostic utility of molecular approaches is the ability to interrogate cell-free nucleic acid of the cyst/duct and/or extracellular fluid. The allelic imbalances at tumor suppressor loci and the selective oncogenic drivers are used clinically to help differentiate benign stable pancreatic cysts from those progressing toward high-grade dysplasia. Methods are discussed and used to determine the efficacy for diagnostic implementation. Here, we report the analytical validation of methods to detect causally associated molecular changes integral to the pathogenesis of pancreatic cancer from pancreatic cyst fluids. Full article