Small non-coding RNAs and pancreatic ductal adenocarcinoma: Linking diagnosis, pathogenesis, drug resistance, and therapeutic potential.

This review comprehensively investigates the intricate interplay between small non-coding RNAs (sncRNAs) and pancreatic ductal adenocarcinoma (PDAC), a devastating malignancy with limited therapeutic options. Our analysis reveals the pivotal roles of sncRNAs in various facets of PDAC biology, spanning diagnosis, pathogenesis, drug resistance, and therapeutic strategies. sncRNAs have emerged as promising biomarkers for PDAC, demonstrating distinct expression profiles in diseased tissues. sncRNA differential expression patterns, often detectable in bodily fluids, hold potential for early and minimally invasive diagnostic approaches. Furthermore, sncRNAs exhibit intricate involvement in PDAC pathogenesis, regulating critical cellular processes such as proliferation, apoptosis, and metastasis. Additionally, mechanistic insights into sncRNA-mediated pathogenic pathways illuminate novel therapeutic targets and interventions. A significant focus of this review is dedicated to unraveling sncRNA mechanisms underlying drug resistance in PDAC. Understanding these mechanisms at the molecular level is imperative for devising strategies to overcome drug resistance. Exploring the therapeutic landscape, we discuss the potential of sncRNAs as therapeutic agents themselves as their ability to modulate gene expression with high specificity renders them attractive candidates for targeted therapy. In summary, this review integrates current knowledge on sncRNAs in PDAC, offering a holistic perspective on their diagnostic, pathogenic, and therapeutic relevance. By elucidating the roles of sncRNAs in PDAC biology, this review provides valuable insights for the development of novel diagnostic tools and targeted therapeutic approaches, crucial for improving the prognosis of PDAC patients.

Development and external validation of a prognostic nomogram to predict survival in patients aged ≥60 years with pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC), which accounts for the vast majority of pancreatic cancer (PC), is a highly aggressive malignancy with a dismal prognosis. Age is shown to be an independent factor affecting survival outcomes in patients with PDAC. Our study aimed to identify prognostic factors and construct a nomogram to predict survival in PDAC patients aged ≥60 years. Methods: Data of PDAC patients aged ≥60 years were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox regression analysis was used to determined prognostic factors of overall survival (OS) and cancer-specific survival (CSS), and two nomograms were constructed and validated by calibration plots, concordance index (C-index) and decision curve analysis (DCA). Additionally, 432 patients from the First Affiliated Hospital of Wenzhou Medical University were included as an external cohort. Kaplan-Meier curves were applied to further verify the clinical validity of the nomograms. Results: Ten independent prognostic factors were identified to establish the nomograms. The C-indexes of the training and validation groups based on the OS nomogram were 0.759 and 0.760, higher than those of the tumor-node-metastasis (TNM) staging system (0.638 and 0.636, respectively). Calibration curves showed high consistency between predictions and observations. Better area under the receiver operator characteristic (ROC) curve (AUC) values and DCA were also obtained compared to the TNM system. The risk stratification based on the nomogram could distinguish patients with different survival risks. Conclusions: We constructed and externally validated a population-based survival-predicting nomogram for PDAC patients aged ≥60 years. The new model could help clinicians personalize survival prediction and risk assessment.

Identifying drug candidates for pancreatic ductal adenocarcinoma based on integrative multiomics analysis.

Background: Due to a lack of early diagnosis methods and effective drugs, pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. DNA methylation, transcriptome expression and gene copy number variation (CNV) have critical relationships with development and progression of various diseases. The purpose of the study was to screen reliable early diagnostic biomarkers and potential drugs based on integrative multiomics analysis. Methods: We used methylation, transcriptome and CNV profiles to build a diagnostic model for PDAC. The protein expression of three model-related genes were externally validated using PDAC samples. Then, potential therapeutic drugs for PDAC were identified by interaction information related to existing drugs and genes. Results: Four significant differentially methylated regions (DMRs) were selected from 589 common DMRs to build a high-performance diagnostic model for PDAC. Then, four hub genes, PHF12, FXYD3, PRKCB and ZNF582, were obtained. The external validation results showed that PHF12, FXYD3 and PRKCB protein expression levels were all upregulated in tumor tissues compared with adjacent normal tissues (P<0.05). Promising candidate drugs with activity against PDAC were screened and repurposed through gene expression analysis of online datasets. The five drugs, including topotecan, PD-0325901, panobinostat, paclitaxel and 17-AAG, with the highest activity among 27 PDAC cell lines were filtered. Conclusions: Overall, the diagnostic model built based on four significant DMRs could accurately distinguish tumor and normal tissues. The five drug candidates might be repurposed as promising therapeutics for particular PDAC patients.

Pancreatic Cancer and Venous Thromboembolism.

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing VTE. Hypoxia in a PDAC tumor microenvironment also elevates thrombotic risk. Direct oral anticoagulants (DOACs) or low-molecular-weight heparin (LMWH) are used only as thromboprophylaxis in PDAC. However, a precision medicine approach is recommended to determine the precise dose and duration of thromboprophylaxis in clinical setting.

Identified γ-glutamyl cyclotransferase (GGCT) as a novel regulator in the progression and immunotherapy of pancreatic ductal adenocarcinoma through multi-omics analysis and experiments.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is renowned for its formidable and lethal nature, earning it a notorious reputation among malignant tumors. Due to its challenging early diagnosis, high malignancy, and resistance to chemotherapy drugs, the treatment of pancreatic cancer has long been exceedingly difficult in the realm of oncology. γ-Glutamyl cyclotransferase (GGCT), a vital enzyme in glutathione metabolism, has been implicated in the proliferation and progression of several tumor types, while the biological function of GGCT in pancreatic ductal adenocarcinoma remains unknown. METHODS: The expression profile of GGCT was validated through western blotting, immunohistochemistry, and RT-qPCR in both pancreatic cancer tissue samples and cell lines. Functional enrichment analyses including GSVA, ssGSEA, GO, and KEGG were conducted to explore the biological role of GGCT. Additionally, CCK8, Edu, colony formation, migration, and invasion assays were employed to evaluate the impact of GGCT on the proliferation and migration abilities of pancreatic cancer cells. Furthermore, the LASSO machine learning algorithm was utilized to develop a prognostic model associated with GGCT. RESULTS: Our study revealed heightened expression of GGCT in pancreatic cancer tissues and cells, suggesting an association with poorer patient prognosis. Additionally, we explored the immunomodulatory effects of GGCT in both pan-cancer and pancreatic cancer contexts, found that GGCT may be associated with immunosuppressive regulation in various types of tumors. Specifically, in patients with high expression of GGCT in pancreatic cancer, there is a reduction in the infiltration of various immune cells, leading to poorer responsiveness to immunotherapy and worse survival rates. In vivo and in vitro assays indicate that downregulation of GGCT markedly suppresses the proliferation and metastasis of pancreatic cancer cells. Moreover, this inhibitory effect appears to be linked to the regulation of GGCT on c-Myc. A prognostic model was constructed based on genes derived from GGCT, demonstrating robust predictive ability for favorable survival prognosis and response to immunotherapy.

Oncological outcomes in minimally invasive vs. open distal pancreatectomy: a systematic review and network meta-analysis.

Background: Advancements in surgical techniques have improved outcomes in patients undergoing pancreatic surgery. To date there have been no meta-analyses comparing robotic and laparoscopic approaches for distal pancreatectomies (DP) in patients with pancreatic adenocarcinoma (PDAC). This systematic review and network meta-analysis aims to explore the oncological outcomes of laparoscopic distal pancreatectomy (LDP), robotic distal pancreatectomy (RDP) and open distal pancreatectomy (ODP). Methods: A systematic search was conducted for studies reporting laparoscopic, robotic or open surgery for DP. Frequentist network meta-analysis of oncological outcomes (overall survival, resection margins, tumor recurrence, examined lymph nodes, administration of adjuvant therapy) were performed. Results: Fifteen studies totalling 9,301 patients were included in the network meta-analysis. 1,946, 605 and 6,750 patients underwent LDP, RDP and ODP respectively. LDP (HR: 0.761, 95% CI: 0.642-0.901, p = 0.002) and RDP (HR: 0.757, 95% CI: 0.617-0.928, p = 0.008) were associated with overall survival (OS) benefit when compared to ODP. LDP (HR: 1.00, 95% CI: 0.793-1.27, p = 0.968) was not associated with OS benefit when compared to RDP. There were no significant differences between LDP, RDP and ODP for resection margins, tumor recurrence, examined lymph nodes and administration of adjuvant therapy. Conclusion: This study highlights the longer OS in both LDP and RDP when compared to ODP for patients with PDAC. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022336417).

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Comparing in vitro cytotoxic drug sensitivity in colon and pancreatic cancer using 2D and 3D cell models: Contrasting viability and growth inhibition in clinically relevant dose and repeated drug cycles.

BACKGROUND: In vitro drug screening that is more translatable to the in vivo tumor environment can reduce both time and cost of cancer drug development. Here we address some of the shortcomings in screening and show how treatment with 5-fluorouracil (5-FU) in 2D and 3D culture models of colorectal cancer (CRC) and pancreatic ductal adenocarcinomas (PDAC) give different responses regarding growth inhibition. METHODS: The sensitivity of the cell lines at clinically relevant 5-FU concentrations was monitored over 4 days of treatment in both 2D and 3D cultures for CRC (SW948 and HCT116) and PDAC (Panc-1 and MIA-Pa-Ca-2) cell lines. The 3D cultures were maintained beyond this point to enable a second treatment cycle at Day 14, following the timeline of a standard clinical 5-FU regimen. RESULTS: Evaluation after one cycle did not reveal significant growth inhibition in any of the CRC or PDAC 2D models. By the end of the second cycle of treatment the CRC spheroids reached 50% inhibition at clinically achievable concentrations in the 3D model, but not in the 2D model. The PDAC models were not sensitive to clinical doses even after two cycles. High content viability metrics point to even lower response in the resistant PDAC models. CONCLUSION: This study reveals the limitations of testing drugs in 2D cancer models and short exposure in 3D models, and the importance of using appropriate growth inhibition analysis. We found that screening with longer exposure and several cycles of treatment in 3D models suggests a more reliable way to assess drug sensitivity.

Novel selective inhibitors of macropinocytosis-dependent growth in pancreatic ductal carcinoma.

Macropinocytosis is a cellular process that enables cells to engulf extracellular material, such as nutrients, growth factors, and even whole cells. It is involved in several physiological functions as well as pathological conditions. In cancer cells, macropinocytosis plays a crucial role in promoting tumor growth and survival under nutrient-limited conditions. In particular KRAS mutations have been identified as main drivers of macropinocytosis in pancreatic, breast, and non-small cell lung cancers. We performed a high-content screening to identify inhibitors of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC)-derived cells, aiming to prevent nutrient scavenging of PDAC tumors. The screening campaign was conducted in a well-known pancreatic KRAS-mutated cell line (MIAPaCa-2) cultured under nutrient deprivation and using FITC-dextran to precisely quantify macropinocytosis. We assembled a collection of 3584 small molecules, including drugs approved by the Food and Drug Administration (FDA), drug-like molecules against molecular targets, kinase-targeted compounds, and molecules designed to hamper protein-protein interactions. We identified 28 molecules that inhibited macropinocytosis, with potency ranging from 0.4 to 29.9 µM (EC50). A few of them interfered with other endocytic pathways, while 11 compounds did not and were therefore considered specific "bona fide" macropinocytosis inhibitors and further characterized. Four compounds (Ivermectin, Tyrphostin A9, LY2090314, and Pyrvinium Pamoate) selectively hampered nutrient scavenging in KRAS-mutated cancer cells. Their ability to impair albumin-dependent proliferation was replicated both in different 2D cell culture systems and 3D organotypic models. These findings provide a new set of compounds specifically targeting macropinocytosis, which could have therapeutic applications in cancer and infectious diseases.

SCANPatient: study protocol for a multi-centre, batched, stepped wedge, comparative effectiveness, randomised clinical trial of synoptic reporting of computerised tomography (CT) scans assessing cancers of the pancreas.

BACKGROUND: Complete surgical removal of pancreatic ductal adenocarcinoma (PDAC) is central to all curative treatment approaches for this aggressive disease, yet this is only possible in patients technically amenable to resection. Hence, an accurate assessment of whether patients are suitable for surgery is of paramount importance. The SCANPatient trial aims to test whether implementing a structured synoptic radiological report results in increased institutional accuracy in defining surgical resectability of non-metastatic PDAC. METHODS: SCANPatient is a batched, stepped wedge, comparative effectiveness, cluster randomised clinical trial. The trial will be conducted at 33 Australian hospitals all of which hold regular multi-disciplinary team meetings (MDMs) to discuss newly diagnosed patients with PDAC. Each site is required to manage a minimum of 20 patients per year (across all stages). Hospitals will be randomised to begin synoptic reporting within a batched, stepped wedge design. Initially all hospitals will continue to use their current reporting method; within each batch, after each 6-month period, a randomly selected group of hospitals will commence using the synoptic reports, until all hospitals are using synoptic reporting. Each hospital will provide data from patients who (i) are aged 18 or older; (ii) have suspected PDAC and have an abdominal CT scan, and (iii) are presented at a participating MDM. Non-metastatic patients will be documented as one of the following categories: (1) locally advanced and surgically unresectable; (2) borderline resectable; or (3) anatomically clearly resectable (Note: Metastatic disease is treated as a separate category). Data collection will last for 36 months in each batch, and a total of 2400 patients will be included. DISCUSSION: Better classifying patients with non-metastatic PDAC as having tumours that are either clearly resectable, borderline or locally advanced and unresectable may improve patient outcomes by optimising care and treatment planning. The borderline resectable group are a small but important cohort in whom surgery with curative intent may be considered; however, inconsistencies with definitions and an understanding of resectability status means these patients are often incorrectly classified and hence overlooked for curative options. TRIAL REGISTRATION: The SCANPatient trial was registered on 17th May 2023 in the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12623000508673).

Free-breathing motion corrected magnetic resonance elastography of the abdomen.

Background: Magnetic resonance elastography (MRE) is a non-invasive method to measure the viscoelastic properties of tissue and has been applied in multiple abdominal organs. However, abdominal MRE suffers from detrimental breathing motion causing misalignment of structures between repeated acquisitions for different MRE dimensions (e.g., motion encoding directions and wave phase offsets). This study investigated motion correction strategies to resolve all breathing motion on sagittal free-breathing MRE acquisitions in a phantom, in healthy volunteers and showed feasibility in patients. Methods: First, in silico experiments were performed on a static phantom dataset with simulated motion. Second, eight healthy volunteers underwent two sagittal MRE acquisitions in the pancreas and right kidney. The multi-frequency free-breathing spin-echo echo-planar-imaging (SE-EPI) MRE consisted of four frequencies (30, 40, 50, 60 Hz), eight wave-phase offsets, with 3 mm3 isotropic voxel size. Following data re-sorting in different number of motion states (4 till 12) based on respiratory waveform signal, three intensity-based registration methods (monomodal, multimodal, and phase correlation) and non-rigid local registration were compared. A ranking method was used to determine the best registration method, based on seven signal-to-noise and image quality measures. Repeatability was assessed for no motion correction (Original) and the best performing method (Best) using Bland-Altman analysis. Lastly, the best motion correction method was compared to no motion correction on patient MRE data [pancreatic ductal adenocarcinoma (PDAC, n=5) and metabolic dysfunction-associated steatotic liver disease (MASLD) (n=1)]. Results: In silico experiments showed a deviation of shear wave speed (SWS) with simulated motion to the ground truth, which was (partially) resolved using motion correction. In healthy volunteers ranking resulted in the best motion correction method of monomodal registration using nine motion states, while no motion correction was ranked last. Limits of agreement were (-0.18, 0.14), and (-0.25, 0.18) m/s for Best and Original, respectively. Using motion correction in patients resulted in a significant increase in SWS in the pancreas (Original: 1.39±0.10 and Best: 1.50±0.17 m/s). After motion correction PDAC had a mean SWS of 1.56±0.27 m/s (Original: 1.42±0.25 m/s). The fibrotic liver mean SWS was 2.07±0.20 m/s (Original: 2.12±0.18 m/s). Conclusions: Motion correction in sagittal free-breathing abdominal MRE results in improved data quality, inversion precision, repeatability, and is feasible in patients.

Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal Adenocarcinoma.

Background: Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its specific effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study aims to investigate how NAT differentially impacts PDAC's carcinoma cells and TME. Methods: Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME between 23 NAT-treated and 13 NAT-naïve PDAC patients, correlating with their clinicopathologic features. Analysis of an online single-nucleus RNA sequencing (snRNA-seq) dataset was performed for validation of the specific cell types responsible for NAT-induced gene expression alterations. Results: NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival. These patients also exhibit increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells, monocytes, and mast cells; and reduced immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement was specifically upregulated in CAFs but not in other stroma cell types. Conclusions: NAT can enhance complement production and signaling within the TME, which is associated with reduced immunosuppression in PDAC. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients.

Solute carrier family 16 member 1 as a potential prognostic factor for pancreatic ductal adenocarcinoma and its influence on tumor immunity.

Background: Solute carrier family 16 member 1 (SLC16A1) serves as a biomarker in numerous types of cancer. Tumor immune infiltration has drawn increasing attention in cancer progression and treatment. The objective of our study was to explore the association between SLC16A1 and the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). Methods: Data were obtained from The Cancer Genome Atlas. The xCell web tool was used to calculate the proportion of immune cells according to SLC16A1 expression. To further explore the mechanism of SLC16A1, immunity-related genes were screened from differentially expressed genes through weighted gene coexpression network analysis, examined via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, and filtrated using univariate Cox regression and least absolute shrinkage and selection operator regression model combined correlation analysis (P<0.05). Next, CIBERSORT was used to analyze the correlation between immune cells and five important genes. SLC16A1 expression and its clinical role in pancreatic cancer was clarified via immunohistochemical staining experiments. Finally, the effects of SLC16A1 on the results of cancer immunity were evaluated by in vitro experiments. Results: SLC16A1 was overexpressed in PDAC tissues and could be an independent prognostic factor. SLC16A1 was significantly negatively correlated with overall survival and suppressed the tumor immunity of PDAC. In clinic, SLC16A1 expression was significantly positively correlated with tumor progression and poor prognosis. We also found that SLC16A1 could suppress the antitumor ability of CD8+ T cells. Conclusions: SLC16A1 is a biomarker for the prognosis of PDAC and can influence the immune environment of PDAC. These findings provide new insights into the treatment of PDAC.

Hidden in plain sight: commonly missed early signs of pancreatic cancer on CT.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis mostly due to the advanced stage at which disease is diagnosed. Early detection of disease at a resectable stage is, therefore, critical for improving outcomes of patients. Prior studies have demonstrated that pancreatic abnormalities may be detected on CT in up to 38% of CT studies 5 years before clinical diagnosis of PDAC. In this review, we highlight commonly missed signs of early PDAC on CT. Broadly, these commonly missed signs consist of small isoattenuating PDAC without contour deformity, isolated pancreatic duct dilatation and cutoff, focal pancreatic enhancement and focal parenchymal atrophy, pancreatitis with underlying PDAC, and vascular encasement. Through providing commentary on demonstrative examples of these signs, we demonstrate how to reduce the risk of missing or misinterpreting radiological features of early PDAC.

Prognostic Value of Histone Acetyl Transferase 1 (HAT-1) and Inflammatory Signatures in Pancreatic Cancer.

Pancreatic cancer is a type of gastrointestinal tumor with a growing incidence and mortality worldwide. Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of cases, and late-stage diagnosis is common, leading to a 5-year survival rate of less than 10% in high-income countries. The use of biomarkers has different proven translational applications, facilitating early diagnosis, accurate prognosis and identification of potential therapeutic targets. Several studies have shown a correlation between the tissue expression levels of various molecules, measured through immunohistochemistry (IHC), and survival rates in PDAC. Following the hallmarks of cancer, epigenetic and metabolic reprogramming, together with immune evasion and tumor-promoted inflammation, plays a critical role in cancer initiation and development. In this study, we aim to explore via IHC and Kaplan-Meier analyses the prognostic value of various epigenetic-related markers (histones 3 and 4 (H3/H4), histone acetyl transferase 1 (HAT-1), Anti-Silencing Function 1 protein (ASF1), Nuclear Autoantigenic Sperm Protein (NASP), Retinol Binding Protein 7 (RBBP7), importin 4 (IPO4) and IPO5), metabolic regulators (Phosphoglycerate mutase (PGAM)) and inflammatory mediators (allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A and IL-18) in patients with PDAC. Also, through a correlation analysis, we have explored the possible interconnections in the expression levels of these molecules. Our results show that higher expression levels of these molecules are directly associated with poorer survival rates in PDAC patients, except in the case of IL-10, which shows an inverse association with mortality. HAT1 was the molecule more clearly associated with mortality, with a hazard risk of 21.74. The correlogram demonstrates an important correlation between almost all molecules studied (except in the case of IL-18), highlighting potential interactions between these molecules. Overall, our study demonstrates the relevance of including different markers from IHC techniques in order to identify unexplored molecules to develop more accurate prognosis methods and possible targeted therapies. Additionally, our correlation analysis reveals potential interactions among these markers, offering insights into PDAC's pathogenesis and paving the way for targeted therapies tailored to individual patient profiles. Future studies should be conducted to confirm the prognostic value of these components in PDAC in a broader sample size, as well as to evaluate the possible biological networks connecting them.

Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway / La cloroxina inhibe la progresión del cáncer de páncreas mediante la antagonización dirigida de la vía de señalización PI3K/AKT/mTOR

Background: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K–AKT–mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. Methods: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. Results: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K–AKT–mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. Conclusions: Chloroxine targeted and inhibited the PI3K–AKT–mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.(AU)

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies.

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as the fourth leading cause of cancer-related deaths in the United States, marked by challenging treatment and dismal prognoses. As immunotherapy emerges as a promising avenue for mitigating PDAC's malignant progression, a comprehensive understanding of the tumor's immunosuppressive characteristics becomes imperative. This paper systematically delves into the intricate immunosuppressive network within PDAC, spotlighting the significant crosstalk between immunosuppressive cells and factors in the hypoxic acidic pancreatic tumor microenvironment. By elucidating these mechanisms, we aim to provide insights into potential immunotherapy strategies and treatment targets, laying the groundwork for future studies on PDAC immunosuppression. Recognizing the profound impact of immunosuppression on PDAC invasion and metastasis, this discussion aims to catalyze the development of more effective and targeted immunotherapies for PDAC patients.

Protein Arginine Methyltransferases in Pancreatic Ductal Adenocarcinoma: New Molecular Targets for Therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant disease with a low 5-year overall survival rate. It is the third-leading cause of cancer-related deaths in the United States. The lack of robust therapeutics, absence of effective biomarkers for early detection, and aggressive nature of the tumor contribute to the high mortality rate of PDAC. Notably, the outcomes of recent immunotherapy and targeted therapy against PDAC remain unsatisfactory, indicating the need for novel therapeutic strategies. One of the newly described molecular features of PDAC is the altered expression of protein arginine methyltransferases (PRMTs). PRMTs are a group of enzymes known to methylate arginine residues in both histone and non-histone proteins, thereby mediating cellular homeostasis in biological systems. Some of the PRMT enzymes are known to be overexpressed in PDAC that promotes tumor progression and chemo-resistance via regulating gene transcription, cellular metabolic processes, RNA metabolism, and epithelial mesenchymal transition (EMT). Small-molecule inhibitors of PRMTs are currently under clinical trials and can potentially become a new generation of anti-cancer drugs. This review aims to provide an overview of the current understanding of PRMTs in PDAC, focusing on their pathological roles and their potential as new therapeutic targets.

The Doppler Perfusion Index of the Liver and the Underlying Duplex Sonography of Visceral Vessels-A Systematic and Comprehensive Evaluation of Reproducibility.

Prior to the curative resection of colorectal carcinoma (CRC) or pancreatic ductal adenocarcinoma (PDAC), the exclusion of hepatic metastasis using cross-sectional imaging is mandatory. The Doppler perfusion index (DPI) of the liver is a promising method for detecting occult liver metastases, but the underlying visceral duplex sonography is critically viewed in terms of its reproducibility. The aim of this study was to investigate systematically the reproducibility of the measured variables, the calculated blood flow, and the DPI. Between February and September 2023, two examinations were performed on 80 subjects within a period of 0-30 days and at two previously defined quality levels, aligned to the German standards of the DEGUM. Correlation analyses were carried out using Pearson's correlation coefficient (PCC) and the intraclass correlation coefficient (ICC). The diameters, blood flow, and DPI showed a high degree of agreement (PCC of 0.9 and ICC of 0.9 for AHP). Provided that a precise standard of procedure is adhered to, the Doppler examination of AHC, AHP, and PV yields very reproducible blood flows and DPI, which is a prerequisite for a comprehensive investigation of its prognostic value for the prediction of metachronous hepatic metastasis in the context of curatively treated CRC or PDAC.