In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens.

Introduction: Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods: Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results: CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion: These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.

Role of glycosylation-related gene MGAT1 in pancreatic ductal adenocarcinoma.

Background: pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a very poor prognosis and a complex tumor microenvironment, which plays a key role in tumor progression and treatment resistance. Glycosylation plays an important role in processes such as cell signaling, immune response and protein stability. Materials and methods: single-cell RNA sequencing data and spatial transcriptome data were obtained from GSE197177 and GSE224411, respectively, and RNA-seq data and survival information were obtained from UCSC Xena and TCGA. Multiple transcriptomic data were comprehensively analyzed to explore the role of glycosylation processes in tumor progression, and functional experiments were performed to assess the effects of MGAT1 overexpression on PDAC cell proliferation and migration. Results: In PDAC tumor samples, the glycosylation level of macrophages was significantly higher than that of normal samples. MGAT1 was identified as a key glycosylation-related gene, and its high expression was associated with better patient prognosis. Overexpression of MGAT1 significantly inhibited the proliferation and migration of PDAC cells and affected intercellular interactions in the tumor microenvironment. Conclusion: MGAT1 plays an important role in PDAC by regulating glycosylation levels in macrophages, influencing tumor progression and improving prognosis.MGAT1 is a potential therapeutic target for PDAC and further studies are needed to develop targeted therapeutic strategies against MGAT1 to improve clinical outcomes.

Main pancreatic duct involved IPMN without high-risk factors: how to judge the degree of malignancy based on MPD dilation?

The aim of this study was to evaluate the cutoff value for identifying malignance in main pancreatic duct (MPD)-involved intraductal papillary mucinous neoplasm (IPMN) with an MPD diameter ranging from 5 to 10 mm. Clinical-radiological characteristics of 142 patients, including MPD-involved IPMNs (n = 53) and branch-duct (BD)-IPMNs (n = 89) were analyzed. Logistic regression analysis was used to determine the risk factors of malignant IPMNs and invasive carcinoma. ROC curves were used to identify different cutoffs in terms of preoperative MPD values to predict the presence of invasive carcinoma as well as malignant IPMNs, and the prediction performance was evaluated. For MPD-involved IPMNs (5 mm < MPD < 10 mm), MPD diameter of 7.5 mm for discriminating malignant IPMNs (area under curve [AUC] = 0.67) and 7.7 mm for discriminating invasive IPMNs (AUC = 0.56) were found to be the optimal cutoff values at receiver operating characteristic curve (ROC) analysis. MPD > 7.5 mm and carbohydrate antigen19-9 (Ca19-9) > 37 U/ml were found to be predictors of malignant IPMNs at univariate, and MPD > 7.5 mm was a predictor in multivariate analysis in MPD-involved IPMNs. The AUC of the ROC curve of MPD (7.5 mm) combined with Ca19-9 in identifying malignant IPMNs was 0.73 in MPD-involved IPMNs. MPD (7.5 mm) combined with Ca19-9 performed well in identifying malignant IPMNs in MPD-involved IPMNs.

The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer.

BACKGROUND: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs. METHODS AND RESULTS: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models. CONCLUSION: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.

Distance-depending transcriptome changes of pancreatic stellate cells in paracrine pancreatic ductal adenocarcinoma co-culture models.

Pancreatic stellate cells (PSC) are one source of cancer-associated fibroblasts (CAF) and play, therefore, an essential role in pancreatic ductal adenocarcinoma (PDA). Paracrine signalling between PDA cells and CAF has been widely studied, yet external influences on paracrine crosstalk are poorly understood. This study aimed to gain a deeper insight into the communication of PSC and cancer cells under different co-culture conditions via analysis of PSC gene expression profiles. Two contactless co-culture models with tumor cells from the p48-Cre; lox-stop-lox-KrasG12D/+; lox-stop-lox-Trp53R172H/+ mouse model (KPC) and murine PSC separated through a microporous membrane and grown in different compartments (standard co-culture) or on different sides of the same membrane (inverse co-culture), were established. RNA-Sequencing analysis of PSC mRNA was performed 24 h and 72 h after co-culture with KPC cells. For selected genes, results were confirmed by quantitative RT-PCR and immunocytochemistry. Standard co-culture displayed 19 differentially expressed genes (DEG) at 24 h and 52 DEG at 72 h. In inverse co-culture, 800 DEG at 24 h and 2213 DEG at 72 h were enriched. PSC showed great heterogeneity in their gene expression profiles; however, mutually regulated genes of both co-cultures, such as VCAN and CHST11, could be identified. VCAN-protein-protein interaction-network analysis revealed several shared genes between co-culture models, such as SDC4 and FN1. In conclusion, PSC show a varying susceptibility to cancer cell signals depending on the co-culture method, with intensified transcriptome changes with closer proximity.

Inhibition of insulin-like growth factors increases production of CXCL9/10 by macrophages and fibroblasts and facilitates CD8+ cytotoxic T cell recruitment to pancreatic tumours.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of in vitro assays and in vivo preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8+ cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8+ T cell recruitment and trafficking towards the PDAC tumour. Exploring this pathway further, we show that IGF inhibition leads to increased STAT1 transcriptional activity, correlating with a downregulation of the AKT/STAT3 signalling axis, in turn promoting Cxcl9 and Cxcl10 gene transcription. Using patient derived tumour explants, we also demonstrate that our findings translate into the human setting. PDAC tumours are frequently described as "immunologically cold", therefore bolstering CD8+ T cell recruitment to PDAC tumours through IGF inhibition may serve to improve the efficacy of immune checkpoint inhibitors which rely on the presence of CD8+ T cells in tumours.

Theranostic nanoparticles for detection and treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most recalcitrant cancers due to its late diagnosis, poor therapeutic response, and highly heterogeneous microenvironment. Nanotechnology has the potential to overcome some of the challenges to improve diagnostics and tumor-specific drug delivery but they have not been plausibly viable in clinical settings. The review focuses on active targeting strategies to enhance pancreatic tumor-specific uptake for nanoparticles. Additionally, this review highlights using actively targeted liposomes, micelles, gold nanoparticles, silica nanoparticles, and iron oxide nanoparticles to improve pancreatic tumor targeting. Active targeting of nanoparticles toward either differentially expressed receptors or PDAC tumor microenvironment (TME) using peptides, antibodies, small molecules, polysaccharides, and hormones has been presented. We focus on microenvironment-based hallmarks of PDAC and the potential for actively targeted nanoparticles to overcome the challenges presented in PDAC. It describes the use of nanoparticles as contrast agents for improved diagnosis and the delivery of chemotherapeutic agents that target various aspects within the TME of PDAC. Additionally, we review emerging nano-contrast agents detected using imaging-based technologies and the role of nanoparticles in energy-based treatments of PDAC. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

AGFG1 increases cholesterol biosynthesis by disrupting intracellular cholesterol homeostasis to promote PDAC progression.

PURPOSE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. EXPERIMENTAL DESIGN: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.

Salicylaldehyde-derived piperazine-functionalized hydrazone ligand-based Pt(II) complexes: inhibition of EZH2-dependent tumorigenesis in pancreatic ductal adenocarcinoma, synergism with PARP inhibitors and enhanced apoptosis.

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Adhesion of pancreatic tumor cell clusters by desmosomal molecules enhances early liver metastases formation.

Desmosomes are intercellular adhesion complexes providing mechanical coupling and tissue integrity. Previously, a correlation of desmosomal molecule expression with invasion and metastasis formation in several tumor entities was described together with a relevance for circulating tumor cell cluster formation. Here, we investigated the contribution of the desmosomal core adhesion molecule desmoglein-2 (DSG2) to the initial steps of liver metastasis formation by pancreatic cancer cells using a novel ex vivo liver perfusion mouse model. We applied the pancreatic ductal adenocarcinoma cell line AsPC-1 with and without a knockout (KO) of DSG2 and generated mouse lines with a hepatocyte-specific KO of the known interacting partners of DSG2 (DSG2 and desmocollin-2). Liver perfusion with DSG2 KO AsPC-1 cells led to smaller circulating cell clusters and a reduced number of cells adhering to murine livers compared to control cells. While this was independent of the expression levels of desmosomal adhesion molecules in hepatocytes, we show that increased cluster size of cancer cells, which correlates with stronger cell-cell adhesion and expression of desmosomal molecules, is a major factor contributing to the early phase of metastatic spreading. In conclusion, impaired desmosomal adhesion results in reduced circulating cell cluster size, which is relevant for seeding and attachment of metastatic cells to the liver.

PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration.

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.

Transcription factor DDIT3 is a potential driver in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and aggressive tumor that affects the digestive tract, leading to high mortality and poor survival rates. The purpose of the present study was to evaluate the expression levels of DNA damage-inducible transcript 3 (DDIT3) in pancreatic cancer and to investigate its effects in in vitro and in vivo experiments. Bioinformatics analysis indicated that DDIT3 expression was higher in pancreatic cancer tumor tissues and associated with a poor prognosis. Positive or strong positive DDIT3 expression was observed in PDAC, and no or weak expression was observed in normal pancreatic tissues. It was also highly expressed in PDAC cells, while being expressed at lower levels in normal pancreatic ductal epithelial cells. Transfection of short hairpin RNA targeting the DDIT3 gene reduced the proliferation, migration and invasion of PANC-1 cells. In vivo, in an in situ implantation tumor model with Pan02 cells, the size and weight of the tumors were reduced in the DDIT3 knockdown Pan02 cell-implanted group. These data suggested that DDIT3 represents a novel predictive biomarker for the potential treatment of patients presenting with PDAC.

NCI SEER-Linked Virtual Tissue Repository Pilot.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) Program with the National Cancer Institute tested whether population-based cancer registries can serve as honest brokers to acquire tissue and data in the SEER-Linked Virtual Tissue Repository (VTR) Pilot. METHODS: We collected formalin-fixed, paraffin-embedded tissue and clinical data from patients with pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC) for two studies comparing cancer cases with highly unusual survival (≥5 years for PDAC and ≤30 months for BC) to pair-matched controls with usual survival (≤2 years for PDAC and ≥5 years for BC). Success was defined as the ability for registries to acquire tissue and data on cancer cases with highly unusual outcomes. RESULTS: Of 98 PDAC and 103 BC matched cases eligible for tissue collection, sources of attrition for tissue collection were tissue being unavailable, control paired with failed case, second control that was not requested, tumor necrosis ≥20%, and low tumor cellularity. In total, tissue meeting the study criteria was obtained for 70 (71%) PDAC and 74 (72%) BC matched cases. For patients with tissue received, clinical data completeness ranged from 59% for CA-19-9 after treatment to >95% for margin status, whether radiation therapy and chemotherapy were administered, and comorbidities. CONCLUSIONS: The VTR Pilot demonstrated the feasibility of using SEER cancer registries as honest brokers to provide tissue and clinical data for secondary use in research. Studies using this program should oversample by 45% to 50% to obtain sufficient sample size and targeted population representation and involve subspecialty matter expert pathologists for tissue selection.

Intraductal and cystic pancreatic neoplasia.

The current WHO classification of digestive system tumours (2019) has presented the concept of diagnostics of intraductal and cystic neoplasms of the pancreas mostly based on integrated molecular data and evaluations of their malignant potential. Intraductal pancreatic neoplasms with ductal phenotype include microscopic precursor lesions of pancreatic ductal adenocarcinoma - the pancreatic intraepithelial neoplasia and macroscopic precursor lesions of pancreatic cancer, where intraductal papillary mucinous neoplasm represents the most common neoplasm of the pancreas with cystic appearance. Both intraductal oncocytic papillary neoplasm and intraductal tubulopapillary neoplasm are now classified as separate entities associated with less aggressive subtypes of pancreatic carcinoma and better prognosis. Clinical significance of microscopic pancreatic intraepithelial neoplasias is limited, in contrast to other intraductal neoplasms, which are presented as cystic and/or solid tumours by imaging methods with important consequences for further treatment and indication of surgical therapy (resection versus "watch and wait" strategies). Neoplasms of nonductal origin, such as acinar cell carcinomas and neuroendocrine neoplasms, can uncommonly display an intraductal growth and their correct classification has a great clinical importance. Moreover, differential diagnostics of cystic pancreatic lesions include not only cystic and pseudocystically transformed neoplasms, but also a large spectrum of reactive, inflammatory and dysontogenetic cystic lesions.

Current diagnostic and treatment options for pancreatic cancer in 2024.

Pancreatic ductal adenocarcinoma is a cancer disease with a very poor prognosis, which poses the third-leading cause of cancer-related deaths and whose incidence and mortality have been predicted to increase significantly in the upcoming years. Almost 80% of patients are diagnosed with advanced unresectable disease and therefore rely on palliative anticancer treatment with limited efficacy. However, even in case of 10-20 % of patients who have successfully undergone radical surgical resection of the localized disease and subsequent adjuvant chemotherapy, the vast majority will relapse within 2-3 years of surgery. The reasons can be found in late diagnosis due to the prolonged clinically asymptomatic course of the disease, complicated anatomical localization, significant tumor heterogeneity, which makes it difficult to test new drugs and, last but not least, in the presence of dense tumor stroma, that complicates the access of cytostatics and targeted drugs into the tumor tissue. Here we present a summary of current treatment options of localized and advanced pancreatic cancer, including molecular diagnostics and targeted treatment of small patients subgroups.

[Synchronous primary multiple cancer: distal cholangiocarcinoma of the intrapancreatic common bile duct and intraductal papillary mucinous tumor associated with ductal adenocarcinoma of the pancreatic tail]. / Sinkhronnyi pervichno-mnozhestvennyi rak: distal'naya kholangiokartsinoma intrapankreaticheskoi chasti obshchego zhelchnogo protoka i vnutriprotokovaya papillyarnaya mutsinoznaya opukhol' v assotsiatsii s protokovoi adenokartsinomoi khvosta podzheludochnoi zhelezy.

We present a combination of distal cholangiocarcinoma of the intrapancreatic common bile duct and intraductal papillary mucinous tumor associated with ductal adenocarcinoma of the pancreatic tail. This clinical case is unique. When analyzing the literature, we found no any case of similar primary multiple malignant tumor. Importantly, final diagnosis of simultaneous malignant pancreatobiliary neoplasia is possible only via intraoperative biopsy after adequate morphological dissection and research of resected organ complex including molecular genetic analysis due to identical histological and immunohistochemical picture of ductal neoplasia.

Repeated Minimally Invasive Pancreatectomy for Intraductal Papillary Mucinous Neoplasm in the Remnant Pancreas: A Case Report.

BACKGROUND Minimally invasive pancreatectomy has become the standard practice for the management of benign and malignant pancreatic tumors. Techniques such as robotic and laparoscopic approaches are known to reduce morbidity by offering benefits such as less blood loss, reduced pain, shorter hospital stays, and quicker recovery times. The indication for repeated minimally invasive pancreatectomy for recurrent or de novo pancreatic neoplasm after primary pancreatic surgery remains debated. CASE REPORT A 50-year-old woman was admitted to our hospital with a diagnosis of an intraductal papillary mucinous neoplasm in the pancreatic head. In 2010, she underwent laparoscopic single-branch resection for a branch-type tumor in the pancreatic uncinate process. During a 5-year follow-up, a de novo intraductal papillary mucinous neoplasm was detected, showing gradual growth and the presence of a mural nodule over the next 7 years. The patient's CEA level was elevated to 7.0 ng/mL. Considering the tumor's progression and the appearance of a mural nodule, we recommended a robot-assisted Whipple procedure. The operation began with laparoscopic adhesiolysis. After detachment of the adhesions and remobilization of the duodenum using the Kocher maneuver, the operation continued with the Da Vinci surgical system. The postoperative period was uneventful, and the patient was discharged on postoperative day 20. Pathological examination revealed intraductal papillary mucinous carcinoma in situ with negative resection margins. CONCLUSIONS This case verifies the safety and feasibility of performing a robotic Whipple procedure for a newly diagnosed pancreatic neoplasm in patients who have previously undergone minimally invasive pancreatic surgery.

INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis.

Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis.

Insights into gemcitabine resistance in pancreatic cancer: association with metabolic reprogramming and TP53 pathogenicity in patient derived xenografts.

BACKGROUND: With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. CONCLUSION: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.

DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression.

Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.