Pancreatic Adenocarcinoma Research Articles

Pancreatic ductal adenocarcinoma (PDAC) lacks consistent biomarkers to monitor treatment response and predict survival. Metabolically active extracellular vesicles (EVs) carrying tumor-specific KRAS mutations offer promise as disease-specific biomarkers. Informed by genomic profiling of tumor tissue, plasma samples were prospectively collected from 44 patients, with confirmed KRAS-mutated PDAC, undergoing neoadjuvant therapy (NAT) followed by surgery between 2019 and 2021. Samples were obtained at diagnosis, post-NAT, and 1month post surgery. EVs were isolated using lipid nanoprobe technology, and EV-associated KRAS mutations were detected using droplet digital polymerase chain reaction (ddPCR). Patients were grouped on the basis of temporal changes in EV-associated KRAS mutation allele frequency (MAF): no KRAS detected (ND), decreasing MAF (DD), and increasing MAF (ID). Among 44 patients, 29 (65.9%) were ND, 8 (18.2%) DD, and 7 (15.9%) ID. Detectable EV-associated KRAS MAF was found in 21%, 30%, and 50% of patients with stages I, II, and III PDAC. No significant differences were noted in demographic or clinical variables (p > 0.05). The ND group had the longest restricted mean disease-free survival (rmDFS: 31.2months), followed by DD (27.8months) and ID (9.8months; p = 0.010). Similarly, restricted mean overall survival (rmOS) was longest in the ND (40.3months), followed by DD (35.7months) and ID (17.7months; p = 0.012). On multivariable analysis, increasing EV-KRAS MAF (ID group) independently predicted inferior rmDFS [hazard ratio (HR): 6.14; p = 0.001] and rmOS (HR: 6.95; p = 0.002). Temporal increase of EV-KRAS MAF is a significant predictor of reduced DFS and OS in PDAC. Integrating EV-KRAS mutation allele frequency dynamics analysis with current biomarkers such as carbohydrate antigen 19-9 (CA19-9) could improve treatment monitoring and survival prognostication.

A vast majority of pancreatic tumors are pancreatic ductal adenocarcinomas that portend a grave prognosis. Non-ductal neoplasms are a small category of pancreatic tumors with different clinical, imaging, and pathological features and a better prognosis compared to adenocarcinoma of the pancreas. Most of the non-ductal neoplasms are surgically resectable when diagnosed early, while a few of them require expectant management. Knowledge of this spectrum of lesions can aid in providing accurate diagnoses and help with radio-pathological correlation. In this review, we wish to present radiological, surgical, and histopathological details of various non-ductal pancreatic neoplasms.

In pancreatic ductal adenocarcinoma, hypoxia is a crucial component of the tumour microenvironment and is associated with worse clinical outcomes. Adaptation to extreme hypoxic settings is based on abnormal lipid metabolism, but insights into how hypoxia-regulated lipid changes link with aggressive migratory potential in pancreatic cancer are lacking. This study investigates the molecular processes, pathways, and critical proteins involved in hypoxia-induced lipidic and polyunsaturated fatty acid alterations in pancreatic cancer. Our findings elucidate increased multilayer unsaturation in FA chains of major lipid classes associated with greater migration and invasion, as well as higher abundances of particular desaturases. The expression of these proteins was verified in clinical tumour samples by unsaturated fatty acid biosynthesis-related gene enrichment score. High unsaturated fatty acid clusters were shown to be associated with a low survival rate. Pathway correlation and protein-protein interaction analysis indicated that the PPAR-hypoxia axis and SCD/FADS2/APOC3-HDLBP protein network are implicated in mediating the observed alterations in lipid pools and poly-unsaturation levels in pancreatic cancer under hypoxia. These results provide novel therapeutic targets in pancreatic cancer while improving our understanding of hypoxia-induced migratory potential in pancreatic cancer.

Gastrointestinal cancers are common malignant tumors posing a serious threat to human health. Irinotecan liposome, a recently approved chemotherapeutic agent primarily indicated for pancreatic cancer within the gastrointestinal malignancies, has seen the publication of numerous high-quality clinical studies with high levels of evidence over the past two years. Scholars continue to explore new clinical applications for this agent. To standardize the clinical application of irinotecan liposomes in gastrointestinal cancers, this expert consensus was developed through multiple rounds of drafting and review led by several specialized committees of the Chinese Anti-Cancer Association, with reference to relevant domestic and international guidelines and the latest evidence-based medical data. This consensus aims to promote rational clinical drug use, prolong patient survival, and provide guidance for the clinical management of gastrointestinal cancers by standardizing chemotherapy regimens, optimizing treatment strategies, and managing adverse events. It details the clinical application strategies, supporting evidence, and adverse event management of irinotecan liposomes in pancreatic, biliary tract, colorectal, and gastric cancers. Furthermore, the consensus addresses key contentious issues-including, but not limited to, dosage, administration, combination therapies, and adverse event management-through expert voting within the oncology field. These deliberations formed the basis for the consensus recommendations provided herein for the reference of clinical practitioners.

Therapeutic cancer vaccines represent a promising immunotherapy approach aimed at treating existing cancers by stimulating the patient’s immune system to target tumor cells. Unlike prophylactic vaccines, therapeutic vaccines are administered after cancer diagnosis and focus on inducing specific cytotoxic CD8 + T cell responses against tumor-associated antigens (TAAs) or tumor-specific neoantigens. These antigens are presented by antigen-presenting cells, such as dendritic cells, to activate an immune attack. However, the efficacy of therapeutic vaccines is often limited by immune tolerance, tumor heterogeneity, and an immunosuppressive tumor microenvironment, necessitating combination with other treatments like immune checkpoint inhibitors or chemotherapy. Multiple vaccine platforms are under investigation including peptide/protein-based, DNA/mRNA-based, dendritic cell vaccines, viral vector vaccines, and personalized neoantigen vaccines that leverage next-generation sequencing for precision targeting. Clinical trials target a range of cancers including melanoma, gynecologic, breast, pancreatic, liver, glioblastoma, and lung cancers, with results showing immune activation but modest clinical efficacy. Key challenges include immune evasion, variability in patient response, manufacturing complexities, high cost, and lack of predictive biomarkers. Technological advances in nanoparticle delivery, potent adjuvants, mRNA platforms, and combination immunotherapies are being explored to enhance vaccine performance. In low-resource settings, barriers such as limited access to advanced diagnostics and clinical trials necessitate tailored strategies to ensure equitable vaccine deployment. Overall, therapeutic cancer vaccines hold potential to become integrated into standard oncology protocols, especially for adjuvant therapy and recurrence prevention, with an emphasis on personalized and accessible immunotherapies to transform cancer management globally.

Invasive intraductal papillary mucinous neoplasms (I-IPMNs) are considered more indolent than conventional pancreatic ductal adenocarcinoma (PDAC). Although neoadjuvant therapy (NAT) is widely adopted in PDAC, its role in I-IPMN remains unclear. This study aimed to evaluate the impact of NAT on survival in I-IPMN compared with PDAC. The study enrolled I-IPMN and PDAC patients undergoing resection at the University of Colorado Hospital between 2013 and 2023. Prognostic factors for overall survival (OS) were identified using Cox models. OS was compared between histology/NAT subgroups using the Kaplan-Meier method and the log-rank test, stratified by resectability. Of 500 patients (413 PDAC, 87 I-IPMN), 289 PDAC and 34 I-IPMN patients received NAT, and the I-IPMN patients showed slightly longer median OS than the PDAC patients (30.2 vs 28.1 months; p = 0.04). In the entire cohort, worse OS was associated with borderline resectable (BR)/locally advanced (LA) disease, elevated cancer antigen 19-9 (CA19-9), node-positive disease, lymphovascular invasion, perineural invasion, and absence of adjuvant therapy. In the resectable cohort (n = 311), NAT was associated with longer OS in PDAC (61.9 vs 34.2 months; p < 0.001), but not in I-IPMN (not reached vs 47.9 months; p = 0.74). Survival did not differ between NAT-treated resectable I-IPMN and PDAC (p = 0.95). In the BR/LA cohort treated with NAT (n = 183), OS was similar between I-IPMN and PDAC (17.1 vs 22.0 months; p = 0.69). In resectable I-IPMN, NAT was not associated with improved survival. Comparable survival between NAT-treated BR/LA I-IPMN and PDAC suggests a need for further research on treatment outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., anti-PD-1 and anti-CTLA-4). In this study, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that although depletion of CSF1R+ myeloid cells in combination with anti-PD-1 and chemotherapy triggers T-cell infiltration into PDA, it also causes compensatory remodeling of the myeloid compartment with limited tumor control. Combination therapy against multiple myeloid targets, including CSF1R, CCR2/5, and CXCR2, was insufficient to overcome treatment resistance. High-dimensional single-cell analyses performed on T-cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T-cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.

Pancreatic adenocarcinoma (PAAD) remains one of the most lethal malignancies, primarily due to its robust resistance to genotoxic therapies, such as chemotherapy and radiotherapy. Understanding the mechanisms underlying this resistance is essential to improve clinical outcomes. Here, we identified trimethylguanosine synthase 1 (TGS1), previously known for its role in RNA modification, as a critical mediator of homologous recombination (HR) repair that specifically contributes to resistance in PAAD. TGS1 was significantly overexpressed in PAAD tissues, correlating strongly with advanced disease stages, therapy resistance, and poor patient prognosis. Following DNA damage, ATM kinase phosphorylated TGS1 at serine residues S389 and S531, which mediated its direct interaction with BRCA1 and subsequent recruitment of BRCA1 to DNA damage sites. The phosphorylation-dependent interaction enhanced HR repair efficiency, enabling cancer cells to survive genotoxic stress. Depletion or pharmacological inhibition of TGS1 induced HR deficiency and markedly enhanced sensitivity to DNA-damaging agents, particularly PARP inhibitors, in PAAD cell lines in vitro and in both cell line-derived and patient-derived xenograft models in vivo. Collectively, these findings uncover an ATM-TGS1-BRCA1 signaling axis that promotes DNA repair and resistance to genotoxic therapies in pancreatic cancer, positioning TGS1 as a promising predictive biomarker and therapeutic target to enhance treatment efficacy.

Magnetoelectric nanoparticles (MENPs), when activated by a magnetic field, are shown to provide a minimally invasive, drug-free, theranostic approach to pancreatic ductal adenocarcinoma (PDAC) treatment. The magnetoelectric effect allows intravenously administered MENPs to be magnetically guided to PDAC xenograft tumors and remotely activated with a 7T-MRI field to induce targeted, electrode-free tumor ablation with real-time imaging feedback. A single MENP treatment achieved a threefold median reduction in tumor volume and complete tumor responses in 33.3% of mice at 300 and 600µg doses (N = 17) and significantly longer mean overall survival as compared to the control cohorts (54.1 vs 28.8 days, χ2 = 40.14, p = 0.045), without evident toxicity in any imaged organ. In contrast, mice receiving subtherapeutic doses, non-activated MENPs, or saline controls showed no significant response. MRI T2* relaxation time decreases closely correlated with tumor reduction (ρ = -0.73, p < 0.001), supporting MENPs as both a therapeutic and imaging biomarker. Mechanistically, MENPs preferentially target cancer cells via magnetic-field-driven electrostatic interactions specific to tumor cell membranes, in agreement with multiphysics numerical simulations. Flow cytometry confirmed that MENP activation primarily induces apoptosis, with minimal necrosis, and time-course studies showed a progressive apoptotic response over 3-hour post-treatment. The findings establish MENPs as a versatile, image-guided, theranostic platform with translational promise for minimally invasive oncology.

This study reports the solvent-free mechanochemical synthesis of a novel series of 2-hydrazone-bridged benzothiazole derivatives 19–52 via the reaction of 2-hydrazinylbenzothiazole derivatives 4–6 with O-alkylated benzaldehydes 7–18. The stereostructure of the E-isomers was confirmed by 2D NOESY spectroscopy. The antiproliferative potential of these newly prepared 2-hydrazone derivatives of benzothiazole 19–52 was evaluated in vitro against eight human cancer cell lines. Several compounds demonstrated low micromolar IC50 values, with some outperforming the reference drug etoposide. Among the most potent compounds, the 6-chloro-2-hydrazone(3-fluorophenyl)benzothiazole derivative 38 exhibited remarkable activity against pancreatic adenocarcinoma (Capan-1, IC50 = 0.6 µM) and non-small cell lung cancer (NCI-H460, IC50 = 0.9 µM). Structure–activity relationship analysis revealed that derivatives 45–52, featuring a methoxy group at position 6 of the benzothiazole ring and either a methoxy or fluorine substituent at position 3 of the phenyl ring, showed consistently strong antiproliferative effects across all tested cell lines (IC50 = 1.3–12.8 µM). Furthermore, compounds bearing N,N-diethylamino or N,N-dimethylamino groups at position 4 of the phenyl ring generally exhibited superior activity compared to those with morpholine or piperidine moieties. However, as this study represents an initial screening, further mechanistic investigations are required to confirm specific anticancer pathways and therapeutic relevance. In addition to their in vitro anticancer properties, the antibacterial activity of the compounds was assessed against both Gram-positive and Gram-negative bacteria. Notably, compound 37 demonstrated selective antibacterial activity against Pseudomonas aeruginosa (MIC = 4 µg/mL). Overall, this work highlights the efficiency of a green, mechanochemical approach for synthesizing E-isomer hydrazone-bridged benzothiazoles and underscores their potential as promising scaffolds for the development of potent antiproliferative agents.

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRASG12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS interactome, aberrant signaling pathways and dysregulated cellular processes contributing to tumorigenesis. This review discusses current knowledge on proteomic alterations associated with oncogenic KRAS mutations, with particular focus on allele-specific proteome signatures and the roles of post-translational modifications (PTMs) of KRAS in modulating the functional networks. Furthermore, we highlight recent therapeutic advances targeting KRAS variants and discuss emerging resistance mechanisms from a proteomics-informed perspective.

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.

Although targeting programmed cell death ligand 1 (PD-L1) has been ineffective in reducing pancreatic ductal adenocarcinoma (PDAC) burden in preclinical and clinical studies, it is unknown if increasing activated CD8+ T-cell numbers, independently or in combination with anti-PD-L1 therapeutics, would improve tumor response. To facilitate evaluation of novel combinatorial strategies targeting PDAC, this study developed a modeling framework to assess therapies targeting PD-L1 and T-cell activation. Chitosan nanoparticles (CNP) loaded with a model antigen have recently shown promising anti-tumor effects by increasing dendritic cell (DC) mediated T-cell activation in a murine PDAC model. Using these in vivo data, along with in vitro and primary and liver metastatic PDAC in situ data, a 3D continuum mixture model of PDAC was rigorously calibrated and solved through distributed computing. The model was applied to analyze the response to anti-PD-L1 and/or antigen-CNP therapies at primary and liver metastatic sites. The results show realistic evaluation of combination therapy targeting PDAC at primary and liver metastatic sites. With the given parameter set, the model projects that anti-PD-L1 therapy and antigen-CNP would synergistically decrease tumor burden at primary and liver metastatic sites to 53.2% and 58.4% of initial burden 5.0 and 5.2 days post-treatment initiation, respectively. Delaying antigen-CNP application 3 or 5 days after anti-PD-L1 and gemcitabine administration further limited metastatic PDAC to <50% of initial burden 15 days post-treatment initiation. In conclusion, the proposed modeling approach enables realistic evaluation of novel combinations of agents, with the goal to design improved PDAC therapy.

Bacteria and tumor debris induced pancreatic cancer progression via the NF-κB signaling pathway.

Plakophilin 3 drives acinar cell transformation and promotes cancer initiation and progression in pancreas.

Identification and validation of BCL11A as a neural and immune vulnerability factor in pancreatic adenocarcinoma.

Sequential YAP1/FOSL1 silencing and epigenetic therapy to overcome stromal barriers in pancreatic cancer.

Molecular, metabolic, and histological subtypes of pancreatic ductal adenocarcinoma and its tumor microenvironment: Insights into tumor heterogeneity and clinical implications.

Co-treatment of ticagrelor and anti-PD-1 immunotherapy in tumor-associated macrophages reduces pancreatic cancer cell growth and migration through the TGF-β1/Smad2 pathway.