Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Analysis of cuproptosis-related lncRNA signature for predicting prognosis and tumor immune microenvironment in pancreatic cancer.

Pancreatic cancer (PC) is a highly malignant digestive tract tumor, with a dismal 5-year survival rate. Recently, cuproptosis was found to be copper-dependent cell death. This work aims to establish a cuproptosis-related lncRNA signature which could predict the prognosis of PC patients and help clinical decision-making. Firstly, cuproptosis-related lncRNAs were identified in the TCGA-PAAD database. Next, a cuproptosis-related lncRNA signature based on five lncRNAs was established. Besides, the ICGC cohort and our samples from 30 PC patients served as external validation groups to verify the predictive power of the risk signature. Then, the expression of CASC8 was verified in PC samples, scRNA-seq dataset CRA001160, and PC cell lines. The correlation between CASC8 and cuproptosis-related genes was validated by Real-Time PCR. Additionally, the roles of CASC8 in PC progression and immune microenvironment characterization were explored by loss-of-function assay. As showed in the results, the prognosis of patients with higher risk scores was prominently worse than that with lower risk scores. Real-Time PCR and single cell analysis suggested that CASC8 was highly expressed in pancreatic cancer and related to cuproptosis. Additionally, gene inhibition of CASC8 impacted the proliferation, apoptosis and migration of PC cells. Furthermore, CASC8 was demonstrated to impact the expression of CD274 and several chemokines, and serve as a key indicator in tumor immune microenvironment characterization. In conclusion, the cuproptosis-related lncRNA signature could provide valuable indications for the prognosis of PC patients, and CASC8 was a candidate biomarker for not only predicting the progression of PC patients but also their antitumor immune responses.

Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma.

BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. RESULTS: Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8+ T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8+ T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. CONCLUSIONS: Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.

Bioinspired Adhesive Antibacterial Hydrogel with Self-Healing and On-Demand Removability for Enhanced Full-Thickness Skin Wound Repair.

Adhesive-caused injury is a great threat for extensive full-thickness skin trauma because extra-strong adhesion can incur unbearable pain and exacerbate trauma upon removal. Herein, inspired by the mussel, we designed and fabricated an adhesive antibacterial hydrogel dressing based on dynamic host-guest interaction that enabled on-demand stimuli-triggered removal to effectively care for wounds. In contrast with most hard-to-removable dressing, this adhesive antibacterial hydrogel exhibited strong adhesion property (85 kPa), which could achieve painless and noninvasive on-demand separation within 2 s through a host-guest competition mechanism (amantadine). At the same time, the hydrogel exhibited rapid self-healing properties, and the broken hydrogel could be completely repaired within 5 min. The hydrogel also had excellent protein adsorption properties, mechanical properties, antibacterial properties, and biocompatibility. This on-demand removal was facilitated by the introduction of amantadine as a competitive guest, without any significant adverse effects on cell activity (>90%) or wound healing (98.5%) in vitro. The full-thickness rat-skin defect model and histomorphological evaluation showed that the hydrogel could significantly promote wound healing and reduce scar formation by regulating inflammation, accelerating skin re-epithelialization, and promoting granulation tissue formation. These results indicate that the developed adhesive antibacterial hydrogel offers a promising therapeutic strategy for the healing of extensive full-layer skin injuries.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). METHODS: We used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS: Our study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. CONCLUSIONS: ADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

HOXA10 promote pancreatic cancer progression via directly activating canonical NF-κB signaling pathway.

BACKGROUND: Although transcription factor homeobox A10 (HOXA10) plays an important role in regulating the development of the pancreas, a pathway of HOXA10 participates in pancreatic ductal adenocarcinoma (PDAC) progression has not been revealed. METHODS: Immunohistochemistry assays were applied to demonstrate the relationship between HOXA10 expression and PDAC progression. Functional assays were used to illustrate the oncogenic role of HOXA10 in PDAC progression. Regulatory mechanisms of HOXA10 induced IKKß gene transcription and the nuclear transcription factor kappa B (NF-κB) signal pathways activation were also investigated in PDAC cells. RESULTS: In the current study, we show that HOXA10 expression increased in PDAC with higher tumor stage and poor patient survival in public RNA-seq data suggesting HOXA10 is associated with PDAC progression. HOXA10 promotes PDAC cell proliferation, anchorage colony formation, and xenograft growth by activating canonical NF-κB signaling both in vitro and in vivo. Mechanically, HOXA10 up-regulates IKKß gene transcription directly and subsequently sustain the activation of NF-κB independent of tumor necrosis factor-alpha in PDAC cells. CONCLUSION: Collectively, up-regulation of HOXA10 gene expression promote cell growth and tumor progression through directly activating canonical NF-κB signaling in PDAC.

Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis.

OBJECTIVE: SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown. DESIGN: TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (PdxcreSetd2flox/flox) together with KrasG12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism. RESULTS: SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis. CONCLUSION: Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.

Patients with hepatic oligometastatic pancreatic body/tail ductal adenocarcinoma may benefit from synchronous resection.

BACKGROUND: Synchronous resection of primary pancreatic ductal adenocarcinoma (PDAC) and liver metastases in highly selective patients is being accepted based on oncology research progress showing safe surgical outcomes with low morbidity and mortality. We also tried to determine patients who would benefit from the operation. METHODS: From January 2012 to October 2017, 48 patients who underwent synchronous resection of primary PDAC and liver metastases were retrospectively evaluated. Twenty-three of them underwent oligometastatic synchronous resection. RESULTS: The majority of synchronous resection PDAC patients underwent hepatic wedge resection, and no oligometastatic patient was treated with hemihepatectomy. The median overall survival (OS) of the synchronous resection patients was 7.8 months. Hepatic oligometastatic PDAC patients had a longer OS than that of non-oligometastatic synchronous resection patients, systemic chemotherapy patients and palliative patients (16.1 vs 6.4 months, P = 0.02; 16.1 vs 7.6 months, P = 0.02; 16.1 vs 4.3 months, P < 0.0001; respectively). Further analysis showed that localized pancreatic body/tail PDAC had a better OS in oligometastatic patients than in non-oligometastatic synchronous resection patients (16.8 months vs 7.05 months, P = 0.0004) and systemic chemotherapy patients (16.8 months vs 8 months, P = 0.003). CONCLUSION: Patients with pancreatic body/tail PDAC with liver oligometastases can benefit from synchronous resection.

Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice.

BACKGROUND & AIMS: Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. METHODS: We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. RESULTS: In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B-LYN-p85 complex, which increased PI3K-Akt-mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. CONCLUSIONS: Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.

Aberrant upregulation of KLK10 promotes metastasis via enhancement of EMT and FAK/SRC/ERK axis in PDAC.

Pancreatic Ductal Adenocarcinoma (PADC) metastasis is the leading cause of morality of this severe malignant tumor. Proteases are key players in the degradation of extracellular matrix which promotes the cascade of tumor metastasis. As a kind of serine proteases, the kallikrein family performs vital function on the cancer proteolysis scene, which have been proved in diverse malignant tumors. However, the specific member of kallikrein family and its function in PDAC remain unexplored. In this study, by data mining of GEO datasets, we have identified KLK10 is upregulated gene in PDAC. We found that KLK10 was significantly overexpressed in tissues of pancreatic intraepithelial neoplasia (PanIN) and PDAC from Pdx1-Cre; LSL-KrasG12D/+ mice (KC) and Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ mice (KPC) by immunohistochemical analysis. Moreover, KLK10 is extremely elevated in the PDAC tissues, especially that from the PDAC patients with lymphatic and distant metastasis. Aberrant KLK10 expression is significantly correlated with poor prognosis and shorter survival by univariable and multivariable analysis. Functionally, knockdown of KLK10 observably inhibits invasion and metastatic phenotype of PDAC cells in vitro and metastasis in vivo. In addition, blockade of KLK10 attenuates epithelial-mesenchymal transition and activation of FAK-SRC-ERK signaling, which explains the mechanism of KLK10 in promoting metastasis. Collectively, KLK10 should be considered as a promising biomarker for diagnosis and potential target for therapy in PDAC.

Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer.

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.

Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma.

To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

Femtosecond laser fabricated micro Mach-Zehnder interferometer with Pd film as sensing materials for hydrogen sensing.

In this paper, a femtosecond laser fabricated fiber inline micro Mach-Zehnder interferometer with deposited palladium film for hydrogen sensing is presented. Simulation results show that the transmission spectrum of the interferometer is critically dependent on the microcavity length and the refractive index of Pd film and a short microcavity length corresponds to a high sensitivity. The experimental results obtained in the wavelength region of 1200-1400 nm, and in the hydrogen concentration range of 0-16%, agree well with that of the simulations. The developed system has high potential in hydrogen sensing with high sensitivity.

A starch-regulated adhesive hydrogel dressing with controllable separation properties for painless dressing change.

The development of hydrogel dressings provides unprecedented opportunities for clinical medicine. However, the traditional hydrogel dressings cannot achieve controllable adhesion and separation, which often brings unbearable pain and secondary damage to patients during removal. In this work, a starch-regulated adhesive hydrogel dressing with controllable separation properties is reported. This hydrogel dressing can achieve rapid separation through the dissociation competition mechanism of polar small molecules, which will not cause any damage or discomfort to the skin or tissues, and greatly facilitate dressing replacement. The adhesive strength of the hydrogel reaches 0.06 MPa, and remains relatively stable after repeated utilization. Meanwhile, the inhibition rate of the hydrogel for E. coli, S. aureus and C. albicans is more than 99.9%. At the same time, the hydrogel also has good swelling properties, mechanical properties and biocompatibility, and exhibits a high healing efficiency (95.01 ± 3.76%) in a rat full-thickness skin defect model. This novel hydrogel dressing with controllable separation properties provides a facile and effective method for wound management and treatment, and has great promise for long-term application of wound dressings.

Increased SPON1 promotes pancreatic ductal adenocarcinoma progression by enhancing IL-6 trans-signalling.

OBJECTIVES: This study investigated the specific molecular mechanism and the roles of extracellular matrix protein Spondin 1 (SPON1) in the development of pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The expression pattern and clinical relevance of SPON1 was determined in GEO, Ren Ji and TCGA datasets, further validated by immunohistochemical staining and Kaplan-Meier analysis. Loss and gain of function experiments were employed to investigate the cellular function of SPON1 in vitro. Gene set enrichment analysis, luciferase assay, immunofluorescence and Western blot and immunoprecipitation were applied to reveal the underlying molecular mechanisms. Subcutaneous xenograft model was used to test the role of SPON1 in tumour growth and maintenance in vivo. RESULTS: SPON1 is significantly upregulated in PDAC tumour tissues and correlated with progression of PDAC. Loss and gain of function experiments showed that SPON1 promotes the growth and colony formation ability of pancreatic cancer cells. Combining bioinformatics assays and experimental signalling evidences, we found that SPON1 can enhance the IL-6/JAK/STAT3 signalling. Mechanistically, SPON1 exerts its oncogenic roles in pancreatic cancer by maintaining IL-6R trans-signalling through stabilizing the interaction of soluble IL-6R (sIL-6R) and glycoprotein-130 (gp130) in PDAC cells. Furthermore, SPON1 depletion greatly reduced the tumour burden, exerted positive effect with gemcitabine, prolonging PDAC mice overall survival. CONCLUSIONS: Our data indicate that SPON1 expression is dramatically increased in PDAC and that SPON1 promotes tumorigenicity by activating the sIL-6R/gp130/STAT3 axis. Collectively, our current work suggests SPON1 may be a potential therapy target for PDAC patient.

SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer.

Owing to the lack of early diagnosis, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal tumours. Because acinar-to-ductal metaplasia (ADM) is a critical process to pancreatic regeneration and PDAC initiation, we applied GSE65146, a dataset composed of transcripts at different time points in wild-type and KrasG12D mutant mice upon pancreatitis induction, to obtain regeneration- and tumour initiation-related genes. By overlapping with genes differentially expressed in human PDAC, we defined the initiation- and progression-related genes, and the most prognostic gene, SULF2, was selected for further verification. By using multiple PDAC genetically engineered murine models (GEMMs), we further verified that the expression of SULF2 was increased at the ADM and PDAC stages. Functionally, SULF2 was able to promote the dedifferentiation of acinar cells as well as the metastatic ability of PDAC. Additionally, our study revealed that SULF2 could enhance TGFß-SMAD signalling via GDF15. More importantly, serum SULF2 was elevated in patients with PDAC, and in combination with CA19-9, it provided a better method for PDAC diagnosis. Herein, our study screened out key genes for the initiation and progression of PDAC, providing potential indicators for the diagnosis of the disease.

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer.

BACKGROUND: Metabolic reprogramming has emerged as a core hallmark of cancer, and cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism. METHODS: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms. RESULTS: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression. CONCLUSIONS: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. RESULTS: We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. CONCLUSION: Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma.

Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC.