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Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Background: Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses resulting from nonspecific early symptoms and the absence of early diagnostic biomarkers. MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, and their abnormal expression is observed in various diseases, including cancer. Cancer stem cells (CSCs) are thought to act as a driving force in PDAC spread and recurrence. In pursuing the goal of unravelling the complexities of PDAC and its underlying molecular mechanisms, our study aimed to identify PDAC-associated miRNAs and relate them to disease progression, focusing on their involvement in various PDAC stages in patients and in reliable in vitro models, including pancreatic CSC (PaCSC) models., Methods: The miRNA profiling datasets of serum and solid biopsies of PDAC patients deposited in GEO DataSets were analyzed by REML-based meta-analysis. The panel was then investigated by Real Time PCR in serum and solid biopsies of 37 PDAC patients enrolled in the study, as well as on BxPC-3 and AsPC-1 PDAC cell lines. We extended our focus towards a possible role of PDAC-associated miRNAs in the CSC phenotype, by inducing CSC-enriched pancreatospheres from BxPC-3 and AsPC-1 PDAC cell lines and performed differential miRNA expression analysis between PaCSCs and monolayer-grown PDAC cell lines., Results: Meta-analysis showed differentially expressed miRNAs in blood samples and cancerous tissues of PDAC patients, allowing the identification of a panel of 9 PDAC-associated miRNAs. The results emerging from our patients fully confirmed the meta-analysis for the majority of miRNAs under investigation. In vitro tasks confirmed the aberrant expression of the panel of PDAC-associated miRNAs, with a dramatic dysregulation in PaCSC models. Notably, PaCSCs have shown significant overexpression of miR-4486, miR-216a-5p, and miR-216b-5p compared to PDAC cell lines, suggesting the recruitment of such miRNAs in stemness-related molecular mechanisms. Globally, our results showed a dual behaviour of miR-216a-5p and miR-216b-5p in PDAC while miR-4486, miR-361-3p, miR-125a-5p, miR-320d expression changes during the disease suggest they could promote PDAC initiation and progression., Conclusions: This study contributed to an enhanced comprehension of the role of miRNAs in the development and progression of PDAC, shedding new light on the miRNA landscape in PDAC and its intricate interplay with CSCs, and providing specific insights useful in the development of miRNA-based diagnostic biomarkers and therapeutic targets., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [OR SD ] = 0.97; 95% confidence interval [CI]: 0.95-0.99, p = 0.006), methionine (OR SD = 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (OR SD = 0.93; 95%CI: 0.87-0.99, p = 0.027), carnitine = (OR SD =1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (OR SD = 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (OR SD = 1.05; 95%CI: 1.01-1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78-0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80-0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis., (© 2024. The Author(s).)

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication, leading to transcription-replication conflicts (TRCs). Here, we demonstrate that TRCs are enriched in human pancreatic ductal adenocarcinoma (PDAC) compared to other common solid tumors or normal cells. Several orthogonal approaches demonstrated that TRCs are oncogene dependent. A small interfering RNA (siRNA) screen identified several factors in the base-excision repair (BER) pathway as main regulators of TRCs in PDAC cells. Inhibitors of BER pathway (methoxyamine and CRT) enhanced TRCs. Mechanistically, BER pathway inhibition severely altered RNA polymerase II (RNAPII) and R-loop dynamics at nascent DNA, causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated the ATR-Chk1 pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chemotherapy resistance has been a great challenge in pancreatic ductal adenocarcinoma(PDAC) treatments. Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen ((5-fluorouracil5-FU), oxaliplatin, Irinotecan) and platinum-based regimens for patients with BRCA mutations. large amounts of work have been done on exploring the mechanism underlying resistance of gemcitabine-based and platinum-based regimens, while little research has been achieved on the mechanism of FOLFIRINOX regimens resistance. Hence, we identified Polypeptide N-Acetylgalactosaminyltransferase 5, (GALNT5) as a vital regulator and a potential therapeutic target in FOLFIRINOX regimens resistance. Colony formation assays and flow cytometry assays were performed to explore the roles of GALNT5 in cell proliferation and apoptosis in PDAC treated with FOLFIRINOX. IC50 alterations were calculated in GALNT5 knockdown and overexpressed cell lines. RNA-seq followed by GSEA (gene set enrichment analysis) was displayed to explore the potential mechanism. WB (western blotting), real-time PCR, and IF (immunofluorescence) were performed to validate relative pathways. The mouse orthotopic xenograft PDAC model was established to examine GALNT5 functions in vivo. GALNT5 was highly expressed in PDAC tissues and predicted poor prognosis in PDAC. Upregulation of GALNT5 in PDAC cells conferred FOLFIRINOX resistance on PDAC by inhibiting DNA damage. Moreover, GALNT5 interacted with MYH9, thus participating in the activation of the NOTCH pathways, resulting in hampering FOI-induced DNA damage. Functions of GALNT5 promoting FOLFIRINOX resistance were validated in vivo. In this study, we found that aberrantly overexpressed GALNT5 in PDAC took part in the activation of the NOTCH pathway by interacting with MYH9, thus inhibiting the DDR to achieve FOLFIRINOX resistance and causing poor prognosis. We identified GALNT5 as a potential therapeutic target for PDAC patients resistant to FOLFIRINOX chemotherapy., (© 2024. The Author(s).)

Clear-cell renal cell carcinoma (ccRCC) is the most common origin of pancreatic metastases (PM). Distinct genomic aberrations, favorable prognosis, and clinical observations on high angiogenesis, and succeeding tyrosine kinase inhibitor (TKI) sensitivity have been reported in PM-ccRCC. However, no functional or single-cell studies have been conducted thus far. We recruited five PM-ccRCC patients and investigated the genomic, single-cell transcriptomic, and drug sensitivity profiles of their patient-derived cells (PDCs). The PM depicted both expected and novel genomic alterations. Further, the transcriptomics differed from both primary and metastatic ccRCC, with upregulations of the PI3K/mTOR and - supporting the clinical observations - angiogenesis pathways. Data integration at pathway level showed that transcriptomics explained drug sensitivities the best. Accordingly, PM-ccRCC PDCs shared sensitivity to many PI3K/mTOR inhibitors. Altogether, we show distinct genomic and transcriptomic signatures in PM-ccRCC, highlight the superiority of transcriptomics in interpreting drug sensitivities, and encourage the use of TKIs and PI3K/mTOR inhibitors in PM-ccRCC., (© 2024. The Author(s).)

Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers. After escaping death, cancer cells are made more metastatic, aggressive, and also drug-resistant through anoikis resistance. The aim of this study is to explore the molecular mechanisms of anoikis-related genes in PAAD and to identify potential key biomarkers. We integrated information about PAAD from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases and identified anoikis-related gene BCL2L1 by survival analysis, univariate Cox regression analysis, and multifactorial Cox regression analysis. Various bioinformatics approaches showed that BCL2L1 was a valuable prognostic marker that might be involved in PAAD development and progression through different mechanisms, including cancer intervention, genomic heterogeneity, and RNA modifications. Our analysis showed that BCL2L1 expression also closely correlates with the expression of various immune checkpoint inhibitors. In particular, we found that long non-coding RNA MIR4435-2HG acted as ceRNA sponging miR-513a-5p to promote the expression of BCL2L1, thereby promoting pancreatic cancer cells proliferation. In conclusion, BCL2L1 expression regulated by the MIR4435-2HG-miR-513a-5p-BCL2L1 ceRNA axis might be used as a biomarker for cancer prognosis, treatment selection, and follow-up in PAAD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is a common malignant tumor of the digestive tract. Although gemcitabine and other therapeutic agents are effective in patients with advanced and metastatic pancreatic cancer, drug resistance has severely limited their use. However, the mechanisms of gemcitabine resistance in pancreatic cancer are poorly understood. In this study, ATAC-seq, ChIP-seq, and RNA-seq were performed to compare chromatin accessibility and gene expression in a patient-derived tumor xenograft (PDX) model of pancreatic cancer with or without gemcitabine resistance. Analyzing these sequencing data, we found a dramatic change in chromatin accessibility in the PDX model of gemcitabine-resistant tissues and identified a key gene, UBR7, which plays an important role in mediating gemcitabine resistance. Further research found that depletion of UBR7 significantly increased pancreatic carcinogenesis and the immunosuppressive microenvironment. Mechanistically, depleted UBR7 increased the stability of PRMT5, thereby promoting glycolysis in pancreatic cancer cells. Finally, an inhibitor that blocks PRMT5 (DS-437) significantly reduced gemcitabine resistance in pancreatic cancer caused by UBR7 depletion. In conclusion, our results illustrate that the UBR7-PRMT5 axis is a key metabolic regulator of PDAC and a promising target for the clinical treatment of gemcitabine resistance in PDAC., (© 2024. The Author(s).)

Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRAS G12D and TP53 R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRAS MUT -dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRAS MUT -dependent manner.

Current therapies against pancreatic ductal adenocarcinoma (PDAC) have limited clinical benefits owing to tumor heterogeneity and their unique immunosuppressive microenvironments. The eukaryotic initiation factor (eIF) 4F complex is involved in regulating translation and various downstream carcinogenic signaling pathways. We report that eIF4G1, one of the subunits of eIF4F, is overexpressed in cancer cells and cancer-associated fibroblasts, and this correlates with poor prognosis in patients with PDAC. In PDAC mice, eIF4G1 inhibition limits tumor progression and prolongs overall survival, especially when combined with PD1/PDL1 antagonists and gemcitabine. Mechanistically, eIF4G1 inhibition hinders the production of cytokines and chemokines that promote fibrosis and inhibit cytotoxic T cell chemotaxis. Moreover, eIF4G1 inhibition impairs integrinβ1 protein translation and exerts tumor suppression effects through the FAK-ERK/AKT signaling pathway. These findings highlight the effects of eIF4G1 on tumor immune dependence and independence and identify eIF4G1 as a promising therapeutic target for PDAC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10 -5 ). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association., (© 2024 UICC.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors that lacks effective treatment options. Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment, associated with tumor progression, prognosis, and treatment response. This work aimed to explore the novel CAFs-associated target to improve treatment strategies in PDAC., Methods: The PDAC single-cell sequencing data (CRA001160, n = 35) were downloaded and integrated based on GSA databases to classify fibroblasts into fine subtypes. Functional enrichment analysis and coexpression regulatory network analysis were used to identify the functional phenotypes and biological properties of the different fibroblast subtypes. Fibroblast differentiation trajectories were constructed using pseudochronological analysis to identify initial and terminally differentiated subtypes of fibroblasts. The changes in the proportions of different fibroblast subtypes before and after PDAC immunotherapy were compared in responsive and nonresponding patients, and the relationships between fibroblast subtypes and PDAC immunotherapy responsiveness were determined based on GSA and GEO database. Using molecular biology methods to confirm the effects of BNIP3 on hypoxia and inflammation in CAFs. CAFs were co cultured with pancreatic cancer cells to detect their effects on migration and invasion of pancreatic cancer., Results: Single-cell data analysis divided fibroblasts into six subtypes. The differentiation trajectory suggested that BNIP3+ Fibro subtype exhibited terminal differentiation, and the expression of genes related to hypoxia and the inflammatory response increased gradually with differentiation time. The specific overexpressed genes in the BNIP3+ Fibro subtype were significantly associated with overall and disease progression-free survival in the patients with PDAC. Interestingly, the greater the proportion of the BNIP3+ Fibro subtype was, the worse the response of PDAC patients to immunotherapy, and the CRTL treatment regimen effectively reduced the proportion of the BNIP3+ Fibro subtype. After knocking out BNIP3, the hypoxia markers and inflammatory factors of CAFs were inhibited. Co-culture of CAFs with pancreatic cancer cells can increase the migration and invasion of pancreatic cancer, but this could be reversed by knocking out BNIP3., Conclusions: This study revealed the BNIP3+ Fibro subtype associated with hypoxia and inflammatory responses, which was closely related to the poor prognosis of patients with PDAC, and identified signature genes that predict the immunotherapy response in PDAC., (© 2024. The Author(s).)

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer's specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer's targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment., (© 2024. The Author(s).)

Resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) leads to ineffective chemotherapy and, consequently, delayed treatment, thereby contributing to poor prognosis. Glycolysis is an important intrinsic reason for gemcitabine resistance as it competitively inhibits gemcitabine activity by promoting deoxycytidine triphosphate accumulation in PDAC. However, biomarkers are lacking to determine which patients can benefit significantly from glycolysis inhibition under the treatment of gemcitabine activity, and a comprehensive understanding of the molecular mechanisms that promote glycolysis in PDAC will contribute to the development of a strategy to sensitize gemcitabine chemotherapy. In this study, we aimed to identify a biomarker that can robustly indicate the intrinsic resistance of PDAC to gemcitabine and guide chemotherapy sensitization strategies. After establishing gemcitabine-resistant cell lines in our laboratory and collecting pancreatic cancer and adjacent normal tissues from gemcitabine-treated patients, we observed that circRNA hsa_circ_0008383 (namely cNEK6) was highly expressed in the peripheral blood and tumor tissues of patients and xenografts with gemcitabine-resistant PDAC. cNEK6 enhanced resistance to gemcitabine by promoting glycolysis in PDAC. Specifically, cNEK6 prevented K48 ubiquitination of small ribonucleoprotein peptide A from the BTRC, a ubiquitin E3 ligase; thus, the accumulated SNRPA stopped PP2Ac translation by binding to its G-quadruplexes in 5' UTR of mRNA. mTORC1 pathway was aberrantly phosphorylated and activated owing to the absence of PP2Ac. The expression level of cNEK6 in the peripheral blood and tumor tissues correlated significantly and positively with the activation of the mTORC1 pathway and degree of glycolysis. Hence, the therapeutic effect of gemcitabine is limited in patients with high cNEK6 levels, and in combination with the mTORC1 inhibitor, rapamycin, can enhance sensitivity to gemcitabine chemotherapy., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths, with adenosquamous carcinoma of the pancreas (ASCP), a rare variant, representing 1-10% of cases. Standard chemotherapy trials for pancreatic cancer exclude ASCP, leaving its optimal treatment uncertain. This report describes a 68-year-old male with metastatic ASCP and a KRAS G12C mutation, progressing through multiple lines of systemic therapy, including targeted inhibition of KRAS G12C. Notably, the patient exhibited a robust response to single-agent immune checkpoint inhibition (ICI) with pembrolizumab, despite intact mismatch repair proteins. The limited success of traditional therapies in pancreatic cancer, coupled with the rarity of ASCP, presents a challenge in establishing effective treatment strategies. While KRAS G12C inhibitors demonstrated modest benefits, this case highlights the remarkable response to ICI in a patient with squamous histology. The distinct tumor microenvironment of ASCP, characterized by squamous differentiation, may contribute to this exceptional response. This underscores the need for further research and clinical trials focused on ICI in ASCP, with an ongoing multi-center phase 2 trial investigating outcomes in this specific subset.

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer.

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2D Low T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2D Low T cell activation, and inhibited NKG2D High T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2D Low T cells was maintained. In vivo xenograft model revealed that NKG2D High T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2D Low T cells within the tumor microenvironment., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, accounting for over 90% of pancreatic cancers, and is characterized by limited treatment options and poor survival rates. Systems biology provides in-depth insights into the molecular mechanisms of PDAC. In this context, novel algorithms and comprehensive strategies are essential for advancing the identification of critical network nodes and therapeutic targets within disease-related protein-protein interaction networks. This study employed a comprehensive computational strategy using the metaheuristic algorithm Trader to enhance the identification of potential therapeutic targets. Analysis of the expression data from the PDAC dataset (GSE132956) involved co-expression analysis and clustering of differentially expressed genes to identify key disease-associated modules. The STRING database was used to construct a network of differentially expressed genes, and the Trader algorithm pinpointed the top 30 DEGs whose removal caused the most significant network disconnections. Enriched gene ontology terms included "Signaling by Rho GTPases," "Signaling by receptor tyrosine kinases," and "immune system." Additionally, nine hub genes-FYN, MAPK3, CDK2, SNRPG, GNAQ, PAK1, LPCAT4, MAP1LC3B, and FBN1-were identified as central to PDAC pathogenesis. This integrated approach, combining co-expression analysis with protein-protein interaction network analysis using a metaheuristic algorithm, provides valuable insights into PDAC mechanisms and highlights several hub genes as potential therapeutic targets., (© 2024. The Author(s).)

In this study, we developed an oleoyl-siRNA conjugate in which oleic acid was conjugated at the 5'-end of the sense strand of the siRNA. Furthermore, we examined the effects of RNAi in a mouse model of pancreatic cancer with liver metastasis. The mouse model of pancreatic cancer with liver metastasis was developed by implanting Sui67Luc human pancreatic cancer cells into the portal veins of mice. Sui67Luc cells have high expression of tumor-related genes such as β -catenin , vascular endothelial growth factor , and programmed cell death ligand-1 . All genes were knocked down using siRNA, among which siRNA targeting β -catenin exhibited the most suitable RNAi effect. Therefore, we investigated the in vitro RNAi effect of oleoyl-siRNA (Ole-siRNA) targeting the β -catenin gene in Sui67Luc cells and found that it was stronger than that of unmodified siRNA. For in vivo experiments, we investigated the biodistribution, antitumor effect, and change in life expectancy of mice upon systemic administration of Ole-siRNA complexed with Invivofectamine 3.0 (IVF). In terms of biodistribution, the Ole-siRNA/IVF complex likely accumulates in the liver of mice. The antitumor effect of Ole-siRNA in a portal vein infusion liver-metastatic Sui67Luc tumor mouse model was evaluated using an in vivo imaging system. Ole-siRNA had a significant antitumor effect compared with nonmodified siRNA. In addition, mice with metastatic liver Sui67Luc tumors treated with Ole-siRNA showed increased survival. These results suggest that Ole-siRNAs are useful novel RNAi molecules for treating pancreatic cancer and liver metastasis.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear., Design: We performed studies with LSL-Kras G12D ; Ptf1a-Cre ERT (KC ERT ) mice or LSL-Kras G12D ; LSL-Trp53 R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice., Results: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1β and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation., Conclusion: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC., (© 2024. The Author(s).)

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment., Methods: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy., Results: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca 2+ -CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival., Conclusions: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression., (© 2024. The Author(s).)

Introduction: Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC)., Methods: In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023., Results: Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P < .0001) as well as during the surveillance period (median DFS: 11.40 months for ctDNA-positive vs NR for ctDNA-negative; HR: 12.38, P < .0001). Additionally, DFS was significantly better with KRAS wildtype status followed by KRASG12R (HR: 0.99, P = .97), KRASG12D (HR: 1.42, P = .194), and worse with KRASG12V (HR: 2.19, P = .002) status. In multivariate analysis, ctDNA detection at surveillance was found to be the most significant prognostic factor for recurrence (HR: 24.28, P < .001)., Conclusions: Perioperative tumor-informed ctDNA detection in PDAC is feasible across all stages and is associated with patient survival outcomes., (© The Author(s) 2024. Published by Oxford University Press.)

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth., (© 2024. The Author(s).)

This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses., (© 2024. The Author(s).)

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology., (© 2024. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer-associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression., Methods: CAAs were generated by co-culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA-conditioned medium (CAA-CM). Small RNA-seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real-time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC., Results: miR-199a-3p expression was significantly increased in CAA-CM-derived exosomes. CAA-derived exosomes transferred miR-199a-3p to pancreatic cancer cells. Transfection with miR-199a-3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR-199a-3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR-199a-3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR-199a is an independent prognostic factor for PDAC., Conclusion: miR-199a-3p in CAA-derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Pancreatic cancer is the fourth leading cause of cancer-related death in both men and women worldwide. The 5-year relative survival rate for pancreatic ductal adenocarcinoma (PDAC) is 10%, which is the lowest among all cancers. This study aimed to find more effective targets to improve the diagnosis, prognostic prediction, and treatment of PDAC., Materials and Methods: Three datasets were selected from the GEO database. Correlation analysis was used to screen the datasets and samples. Differentially expressed genes were identified using GEO2R. Metascape was used to perform pathway and process enrichment analysis. Survival analysis using the GEPIA2 and Kaplan-Meier plotter databases was conducted to filter hub genes. Principal component analysis and LASSO regression analyses were used to further filter the key genes. Gene expression in PDAC and normal tissues and in different pathological stages was analyzed using the GEPIA2 database. Thereafter, gene expression was detected in three PDAC and HPDE cell lines using real-time polymerase chain reaction., Results: LPAR5, CYP2C18, SERPINH1, ACSL5, and HCAR3 exhibited higher transcription levels in PDAC tissues compared to matched normal tissues, whereas the PNLIP expression was lower. LPAR5, CYP2C18, SERPINH1 and ACSL5 were markedly upregulated in stage IV PDAC. LPAR5, CYP2C18, SERPINH1 and ACSL5 were upregulated in PDAC cell lines. Further verification suggested that the expression levels of these four genes were closely related to histological type, pathologic stage, therapeutic effects and prognosis of pancreatic cancer., Conclusion: LPAR5, CYP2C18, SERPINH1 and ACSL5 may serve as potential diagnostic, prognostic, and therapeutic targets for PDAC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Patients with synchronous pancreatic ductal adenocarcinoma (PDAC) and nasopharyngeal carcinoma (NPC) have not been previously reported in the English literature. We present such a unique case with both PDAC and NPC., Case Report: A 72-year-old Asian-American female with a past medical history of primary biliary cholangitis presented with abdominal pain. Initial computer tomography (CT) scans demonstrated a 13 cm solid and cystic mass in the pancreatic body and tail with no mass identified in her liver. A biopsy of the pancreatic mass revealed pancreatic duct adenocarcinoma. Further evaluation with a positron emission tomography (PET) scan revealed a hypermetabolic mass (SUVmax10) in the nasopharynx. Subsequent biopsy results were consistent with nasopharyngeal carcinoma. Genetic counseling and next-generation sequencing (NGS) on her peripheral blood DNA were performed, identifying a pathogenic mutation of ATM c.8545C>T (p.Arg2849*). The patient was treated with gemcitabine-abraxane chemotherapy and FOLFIRINOX (fluorouracil, oxaliplatin, leucovorin and irinotecan) for her PDAC, while radiation therapy was proposed for her NPC. Ultimately, due to the progression of the malignancies, she entered hospice care and passed eight months after the diagnosis of PDAC., Conclusion: To the best of our knowledge, this is the first documented case of synchronous PDAC and NPC in a patient with novel associated pathogenic ATM c.8545C>T (p.Arg2849*) mutation and poor prognosis. More similar case reports are needed to further characterize this entity., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Targeting checkpoints for immune cell activation has been acknowledged known as one of the most effective way to activate anti-tumor immune responses. Among them, drugs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for clinical treatment though several more are in advanced stages of development, which demonstrated durable response rates and manageable safety profile. However, its therapy efficacy is unsatisfactory in pancreatic cancer (PC), which can be limited by the overall condition of patients, the pathological type of PC, the expression level of tumor related genes, etc. To improve clinical efficiency, various researches have been conducted, and the efficacy of combination therapy showed significantly improvement compared to monotherapy. This review analyzed current strategies based on anti-CTLA-4 combination immunotherapy, providing totally new idea for future research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Pancreatic cancer (PC) is a complex malignancy, distinguished by its aggressive characteristics and unfavorable prognosis. Recent developments in understanding the molecular foundations of this disease have brought attention to the noteworthy involvement of microRNAs (miRNAs) in disease development, advancement, and treatment resistance. The anticancer capabilities of flavonoids, which are a wide range of phytochemicals present in fruits and vegetables, have attracted considerable interest because of their ability to regulate miRNA expression. This review provides the effects of flavonoids on miRNA expression in PC, explains the underlying processes, and explores the possible therapeutic benefits of flavonoid-based therapies. Flavonoids inhibit PC cell proliferation, induce apoptosis, and enhance chemosensitivity via the modulation of miRNAs involved in carcinogenesis. Additionally, this review emphasizes the significance of certain miRNAs as targets of flavonoid action. These miRNAs have a role in regulating important signaling pathways such as the phosphoinositide-3-kinase-protein kinase B/Protein kinase B (Akt), mitogen activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Wnt/β-catenin pathways. This review aims to consolidate current knowledge on the interaction between flavonoids and miRNAs in PC, providing a comprehensive analysis of how flavonoid-mediated modulation of miRNA expression could influence cancer progression and therapy. It highlights the use of flavonoid nanoformulations to enhance stability, increase absorption, and maximize anti-PC activity, improving patient outcomes. The review calls for further research to optimize the use of flavonoid nanoformulations in clinical trials, leading to innovative treatment strategies and more effective approaches for PC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript. Conflicts of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Outcomes from pancreatic ductal adenocarcinoma (PDAC) remain poor and better methods of prognostication and therapeutic approaches are needed. Recent advances in cancer genomics have led to the development of molecular subtypes of PDAC associated with clinical outcomes. Current evidence also suggests that the subtypes have differential response to first-line chemotherapy regimens. PDAC is also characterized by different stroma and immune environments. Further work is needed to confirm the utility of these subtypes to predicting response to different systemic therapies., Competing Interests: Disclosure PurIST was licensed to GeneCentric Therapeutics Inc (JJY). Funding JJY is supported by R01 CA199064, U01 CA274298, U24 CA211000, and P50 CA257911., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Early detection of pancreatic cancer has been shown to improve patient survival rates. However, effective early detection tools to detect pancreatic cancer do not currently exist. The Avantect Pancreatic Cancer Test, leveraging the 5-hydroxymethylation [5-hydroxymethylcytosine (5hmC)] signatures in cell-free DNA, was developed and analytically validated to address this unmet need. We report a comprehensive analytical validation study encompassing precision, sample stability, limit of detection, interfering substance studies, and a comparison with an alternative method. The assay performance on an independent case-control patient cohort was previously reported with a sensitivity for early-stage (stage I/II) pancreatic cancer of 68.3% (95% CI, 51.9%-81.9%) and an overall specificity of 96.9% (95% CI, 96.1%-97.7%). Precision studies showed a cancer classification of 100% concordance in biological replicates. The sample stability studies revealed stable assay performance for up to 7 days after blood collection. The limit of detection studies revealed equal results between early- and late-stage cancer samples, emphasizing strong early-stage performance characteristics. Comparisons of concordance of the Avantect assay with the enzymatic methyl sequencing (EM-Seq) method, which measures both methylation (5-methylcytosine) and 5hmC, were >95% for all samples tested. The Avantect Pancreatic Cancer Test showed strong analytical validation in multiple validation studies required for laboratory-developed test accreditation. The comparison of 5hmC versus EM-Seq further validated the 5hmC approach as a robust and reproducible assay., Competing Interests: Disclosure Statement All authors are employees of ClearNote Health., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Mucinous cystic neoplasm (MCN) is one of the precursor lesions of pancreatic ductal adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to examine the presence of short telomeres in promoting the tumorigenesis of MCN by measuring telomere lengths in distinct components of MCN, including the mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma. A total of 45 patients with MCN (30 pancreatic and 15 hepatic cases) were obtained. Quantitative telomere-specific fluorescent in situ hybridization was performed to measure the telomere length of specific cell types within MCNs, including mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma, as well as normal ductal epithelium and adenocarcinoma. Relative telomere lengths tended to decrease between normal ductal epithelium, ovarian-type stroma, non-mucinous lining epithelium, mucinous lining epithelium, and adenocarcinoma regardless of the involved organs. Among the analyzed cell types, relative telomere lengths were significantly different between normal ductal epithelium (3.31 ± 0.78), ovarian-type stroma (2.90 ± 0.93), non-mucinous lining epithelium (2.84 ± 0.79), mucinous lining epithelium (2.49 ± 0.93), and adenocarcinoma (1.19 ± 0.59), respectively (P < 0.001, mixed-effects model). As expected, no difference in relative telomere lengths was observed between normal ductal epithelium and ovarian-type stroma; however, significant differences were observed in pair-wise comparisons between ovarian-type stroma vs. non-mucinous lining epithelium (P = 0.001), non-mucinous lining epithelium vs. mucinous lining epithelium (P = 0.005), and mucinous lining epithelium vs. adenocarcinoma (P < 0.001). These findings suggest gradual telomere shortening occurs in the tumorigenesis of MCN, which may have important implications for the progression of this disease., Competing Interests: Declaration of competing interest The authors declare no competing financial interests with respect to the research., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC., Methods: We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360., Results: Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis., Conclusion: Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers., Methods: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort., Results: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%)., Conclusions: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer., (© 2024. The Author(s).)

Alkaliptosis is a type of pH-dependent cell death and plays an emerging role in tumor suppression. However, the key modulation mechanism of alkaliptosis remains largely unknown. In particular, the nucleus, as the centre of genetic and metabolic regulation, is crucial for the regulation of cellular life. It is not known whether nuclear proteins are involved in the regulation of alkaliptosis. Here, we isolated nuclear proteins to perform a proteomics that identified itchy E3 ubiquitin protein ligase (ITCH) as a natural inhibitor of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. The downregulation of ITCH protein is associated with the induction of alkaliptosis in three human PDAC cell lines (SW1990, MiaPaCa2, and PANC1). Functionally, increasing ITCH expression reduces JTC801-induced growth inhibition and cell death. In contrast, knocking down ITCH using specific shRNA increases JTC801-induced cell growth inhibition in the short or long term, resulting in increased cell death. Mechanistically, JTC801-induced ITCH inhibition blocks large tumor suppressor kinase 1 (LATS1) ubiquitination, which in turn suppresses Yes1 associated transcriptional regulator (YAP1)-dependent the transcriptional activation of solute carrier family 16 member 1 (SLC16A1), a proton-linked monocarboxylate transporter that inhibits JTC801-induced alkaliptosis. Additionally, decreased expression of ITCH is associated with longer survival times in patients with PDAC. Collectively, our results establish an ITCH-dependent pathway that regulates alkaliptotic sensitivity in PDAC cells and deepen the understanding of alkaliptosis in targeted therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest or financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFβ drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC., (©2024 American Association for Cancer Research.)

Neuroendocrine tumors (NETs) are a rare, heterogenous group of neoplasms arising from cells of the neuroendocrine system. Amongst solid tumor malignancies, NETs are notable for overall genetic stability and recent data supports the notion that epigenetic changes may drive NET pathogenesis. In this review, major epigenetic mechanisms of NET pathogenesis are reviewed, including changes in DNA methylation, histone modification, chromatin remodeling, and microRNA. Prognostic implications of the above are discussed, as well as the expanding diagnostic utility of epigenetic markers in NETs. Lastly, preclinical and clinical evaluations of epigenetically targeted therapies in NETs and are reviewed, with a focus on future directions in therapeutic advancement., Competing Interests: Declaration of competing interest I, Hannah McMurry, do not have and financial/personal competing interests related to the contents of the submitted manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery., Methods: The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil., Results: The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells., Conclusions: TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and lack of biomarkers. A rich desmoplastic tumor stroma is considered a hallmark of PDAC and previous studies have indicated upregulated expression of collagen VI (COL6) in PDAC. COL6 is shown to associate with prognosis in many cancers but has been less extensively studied in PDAC., Materials and Methods: The expression of COL6 was analyzed by immunohistochemistry in tissue microarrays containing resected tumor tissue samples from PDAC patients (n = 164). Significance of COL6 was estimated with Kaplan-Meier survival estimates and multivariable Cox regression analysis. COL6 protein and mRNA expression patterns were further investigated in publicly available datasets., Results: There were no statistically significant ( P < 0.05) differences in survival when comparing high and low protein expression of any of the analyzed COL6 α-chains (α1(VI): hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.64-1.28; α2(VI): HR 1.28, 95% CI 0.86-1.89; α3(VI): HR 0.91, 95% CI 0.64-1.29). Similar results were obtained when assessing public data from the Cancer Proteome Atlas, Clinical Proteomic Tumor Analysis Consortium, and The Cancer Genome Atlas., Conclusions: In contrast with previous studies and some other cancers, we did not find any association of COL6 tissue expression and PDAC survival., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

MYC has been identified to profoundly influence a wide range of pathologic processes in cancers. However, the prognostic value of MYC-related genes in pancreatic adenocarcinoma (PAAD) remains unclarified. Gene expression data and clinical information of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database (training set). Validation sets included GSE57495, GSE62452, and ICGC-PACA databases. LASSO regression analysis was used to develop a risk signature for survival prediction. Single-cell sequencing data from GSE154778 and CRA001160 datasets were analyzed. Functional studies were conducted using siRNA targeting RHOF and ITGB6 in PANC-1 cells. High MYC expression was found to be significantly associated with a poor prognosis in patients with PAAD. Additionally, we identified seven genes (ADGRG6, LINC00941, RHOF, SERPINB5, INSYN2B, ITGB6, and DEPDC1) that exhibited a strong correlation with both MYC expression and patient survival. They were then utilized to establish a risk model (MYCsig), which showed robust predictive ability. Furthermore, MYCsig demonstrated a positive correlation with the expression of HLA genes and immune checkpoints, as well as the chemotherapy response of PAAD. RHOF and ITGB6, expressed mainly in malignant cells, were identified as key oncogenes regulating chemosensitivity through EMT. Downregulation of RHOF and ITGB6 reduced cell proliferation and invasion in PANC-1 cells. The developed MYCsig demonstrates its potential in enhancing the management of patients with PAAD by facilitating risk assessment and predicting response to adjuvant chemotherapy. Additionally, our study identifies RHOF and ITGB6 as novel oncogenes linked to EMT and chemoresistance in PAAD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To investigate the inhibitory effect of LNCNA-NEA1 on pancreatic cancer development and progression via spongiosa miR-146b-5p/TRAF6, 60 pancreatic cancer patients diagnosed from December 2017 to December 2019 were selected as a general source of information. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect the expression level of NEAT1 in cancerous and adjacent non-cancerous tissues. Cell counting kit-8 (CCK-8) and transwell were used to determine the effect of LNCNA-NEA1 on the proliferation and migration of pancreatic cancer cells (Panc-1). The results of dual luciferase reporter gene assay showed that nea 1 could target and regulate the expression of spongy miR-146b-5p/TRAF6, and reducing the expression of spongy miR-146b-5p/TRAF6 could reverse the inhibitory effects of nea 1-siRNA on proliferation, migration and invasion of pancreatic cancer cells. Therefore, it was concluded that knockdown of nea 1 could inhibit the proliferation, migration and invasion of pancreatic cancer cells by upregulating the level of miR-146b-5p/TRAF6, and the expression of lnc RNA-nea 1 could be used as an indicator for preoperative diagnosis and postoperative prognosis of pancreatic cancer patients.      .

Pancreatic acinar cell carcinoma (PACC) is a rare type of pancreatic cancer; further, its pathogenesis and treatment strategies remain unclear. We report the case of a 70-year-old man who presented with a chief complaint of abdominal distention. Computed tomography scans revealed a large lobulated mass (tumor diameter: 150 mm) in the pancreatic body tail, which was diagnosed as a PACC through endoscopic ultrasonography fine needle aspiration. The other imaging modalities did not reveal distant metastases, and the tumor was classified as resectable. Neoadjuvant chemotherapy was planned after staging laparoscopy ruled out microscopic distant metastasis. First-line chemotherapy with gemcitabine + nab-paclitaxel failed due to tumor growth and worsening abdominal distention. Evaluation using the BRACAnalysis ® device indicated that the patient was positive for BRCA1 mutation. Second-line modified FOLFIRINOX (mFFX) resulted in a marked decrease in elastase 1 levels; moreover, a partial antitumor response was observed, which prompted radical resection. After distal pancreatectomy, the patient has survived for 3.5 years without recurrence. BRCA-mutated pancreatic cancer is more likely to respond to mFFX, including platinum, and BRCA mutations have been reported to be highly prevalent in PACC. It is important to evaluate the presence of BRCA mutations in patients with PACC prior to treatment., (© 2024. Japanese Society of Gastroenterology.)

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is infrequent. Currently, non-invasive biomarkers for early detection of PDAC are not accessible. Here, we intended to identify a set of urine markers able to discriminate patients with early-stage PDAC from healthy individuals., Patients and Methods: Seventy-five urine samples from PDAC patients and 50 healthy controls were assayed using quantitative real-time PCR (qPCR). The chosen biomarkers were lymphatic vessel endothelial HA receptor (LYVE-1), regenerating islet-derived 1 alpha (REG1A), and trefoil factor family (TFF1)., Results: LYVE-1, REG1A, and TFF1 expression in PDAC proved to be significantly elevated compared to healthy individuals (p < 0.05). Determination of these markers' expression might be useful for early tumor diagnosis with a sensitivity of 96 %, 100 %, and 73.33 % respectively, and a specificity of 100 %, 82 %, and 100 % respectively., Conclusion: We have recognized three diagnostic biomarkers REG1A, TFF1, and LYVE1 that can detect patients with early-stage pancreatic cancer in non-invasive urine specimens with improved sensitivity and specificity. To the best of our knowledge, there have been no prior investigations examining the mRNA expression levels of them in urine within the Egyptian population., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)