CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m6A) modification.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells. METHODS: We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (m6A) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens. RESULTS: Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating m6A modification via vir-like m6A methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC. CONCLUSIONS: In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via m6A-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC.

Cancer-specific survival in patients with cholangiocarcinoma after radical surgery: a Novel, dynamic nomogram based on clinicopathological features and serum markers.

BACKGROUND: This study aims to (1) identify preoperative testing-based characteristics associated with enhanced prognosis and survival for cholangiocarcinoma patients, and (2)create a distinctive nomogram to anticipate each patient's cancer-specific survival (CSS). METHODS: Retrospective analysis was performed on 197 CCA patients who underwent radical surgery at Sun Yat-sen Memorial Hospital; they were divided into a 131-person "training cohort" and a 66-person "internal validation cohort." The prognostic nomogram was created following a preliminary Cox proportional hazard regression search for independent factors influencing the patients' CSS. Its applicable domain was examined via an external validation cohort, which included 235 patients from the Sun Yat-sen University Cancer Center. RESULTS: The median follow-up period for the 131 patients in the training group was 49.3 months (range, 9.3 to 133.9 months). One-, three-, and five-year CSS rates were 68.7%, 24.5%, and 9.2%, respectively, with the median CSS length being 27.4 months (range: 1.4 to 125.2 months). PLT, CEA, AFP, tumor location, differentiation, lymph node metastasis, chemotherapy, and TNM stage were determined to be independent risk factors for CCA patients by univariate and multivariate Cox proportional hazard regression analysis. We were able to accurately predict postoperative CSS after incorporating all of these characteristics into a nomogram. The AJCC's 8th edition staging method's C-indices were statistically substantially (P < 0.001) lower than the nomogram's C-indices (0.84, 0.77, and 0.74 in the training, internal and external validation cohorts respectively). CONCLUSIONS: A realistic and useful model for clinical decision-making and the optimization of therapy is presented as a nomogram that includes serum markers and clinicopathologic features for predicting postoperative survival in cholangiocarcinoma.

Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification.

BACKGROUND: Perineural invasion (PNI) has a high incidence and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Our study aimed to identify the underlying molecular mechanism of PNI and propose effective intervention strategies. METHODS: To observe PNI in vitro and in vivo, a Matrigel/ dorsal root ganglia (DRG) model and a murine sciatic nerve invasion model were respectively used. Magnetic resonance (MR) imaging and positron emission tomography/computed tomography (PET-CT) imaging were also used to evaluate tumor growth. Publicly available datasets and PDAC tissues were used to verify how the nerve cells regulate PDAC cells' PNI. RESULTS: Our results showed that glutamate from nerve cells could cause calcium influx in PDAC cells via the N-methyl-d-aspartate receptor (NMDAR), subsequently activating the downstream Ca2+ dependent protein kinase CaMKII/ERK-MAPK pathway and promoting the mRNA transcription of gene METTL3. Next, METTL3 upregulates the expression of hexokinase 2 (HK2) through N6-methyladenosine (m6A) modification in mRNA, enhances the PDAC cells' glycolysis, and promotes PNI. Furthermore, the IONPs-PEG-scFvCD44v6-scAbNMDAR2B nanoparticles dual targeting CD44 variant isoform 6 (CD44v6) and t NMDAR subunit 2B (NMDAR2B) on PDAC cells were synthesized and verified showing a satisfactory blocking effect on PNI. CONCLUSIONS: Here, we firstly provided evidence that glutamate from the nerve cells could upregulate the expression of HK2 through mRNA m6A modification via NMDAR2B and downstream Ca2+ dependent CaMKII/ERK-MAPK pathway, enhance the glycolysis in PDAC cells, and ultimately promote PNI. In addition, the dual targeting nanoparticles we synthesized were verified to block PNI effectively in PDAC.

Cascade and Fusion: A Deep Learning Approach for Camouflaged Object Sensing.

The demand for the sensor-based detection of camouflage objects widely exists in biological research, remote sensing, and military applications. However, the performance of traditional object detection algorithms is limited, as they are incapable of extracting informative parts from low signal-to-noise ratio features. To address this problem, we propose Camouflaged Object Detection with Cascade and Feedback Fusion (CODCEF), a deep learning framework based on an RGB optical sensor that leverages a cascaded structure with Feedback Partial Decoders (FPD) instead of a traditional encoder-decoder structure. Through a selective fusion strategy and feedback loop, FPD reduces the loss of information and the interference of noises in the process of feature interweaving. Furthermore, we introduce Pixel Perception Fusion (PPF) loss, which aims to pay more attention to local pixels that might become the edges of an object. Experimental results on an edge device show that CODCEF achieved competitive results compared with 10 state-of-the-art methods.

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer.

BACKGROUND: We previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP. METHODS: Microarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. RESULTS: The downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155. CONCLUSIONS: Bmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.

Expression of the PTEN/FOXO3a/PLZF signalling pathway in pancreatic cancer and its significance in tumourigenesis and progression.

Pancreatic cancer (PC) is one of the most lethal gastrointestinal malignancies. The PTEN/AKT signalling pathway is closely related to the tumourigenesis and progression of PC. The downstream effectors, FOXO3a, PLZF and VEGF, are reported to be involved in angiogenesis, lymph node metastasis and poor survival in PC. By using tissue microarrays and immunohistochemistry, we found, that PTEN, FOXO3a and PLZF expression was significantly decreased in PC specimens compared with that in chronic pancreatitis (CP) specimens, while VEGF expression was significantly increased. Furthermore, the expression of PTEN was positively correlated with that of FOXO3a and PLZF but negatively correlated with that of VEGF. Our results suggest that the PTEN/FOXO3a/PLZF signalling pathway may negatively regulate VEGF expression in PC. Through clinical analysis of 69 PC patients, PTEN, FOXO3a and PLZF expression was found to be significantly decreased in specimens from PC patients with lymph node metastasis and poor prognosis, while VEGF expression was significantly increased. Taken together, these reaults suggest that the PTEN/FOXO3a/PLZF signalling pathway may be capable of inhibiting growth and metastasis in PC by regulating VEGF-mediated angiogenesis, which requires further in vivo and in vitro studies and can potentially be a therapeutic target for PC.

KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.

Oncogenic KRAS plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. However, the mechanism has not been clearly elucidated. RKIP is a tumor repressor, and loss of RKIP has been shown in PDAC. Here, we found that KRAS expression was inversely correlated with RKIP expression in PDAC fresh tissue regardless of the KRAS mutant status. The negative correlation between KRAS and RKIP was further confirmed in our PDAC tissue microarray. KRAS overexpression and RKIP downregulation were associated with poor clinical outcomes. Knockdown or overexpression of KRAS in PDAC cell lines robustly increased or decreased, respectively, RKIP protein and mRNA levels. Furthermore, the MAPK-ERK pathway was involved in the regulation of RKIP. KRAS-regulated RKIP expression, which in turn affected the expression of pivotal epithelial-mesenchymal transition (EMT) and apoptosis factors. The biological function of the KRAS-RKIP axis was demonstrated in human pancreatic cancer cells in vitro and in vivo. KRAS knockdown increased RKIP expression and inhibited metastasis and chemoresistance. Moreover, the feature of metastasis and chemoresistance was rescued in the KRAS-knockdown cells through the inhibition of RKIP by RNA interference. In conclusion, our studies demonstrate how KRAS inhibits the tumor suppressor RKIP, thus offering novel justification for targeting RKIP as a strategy to overcome KRAS-induced tumor metastasis and chemoresistance in PDAC.

Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.

Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.

Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.

It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.

BACKGROUND: B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP) are involved in cancer metastasis and chemotherapeutic resistance, respectively. In this study, we evaluated the association between Bmi-1 and RKIP and outcome of gastric cancer through clinical data analysis and in vitro experiments. METHODS: Bmi-1 expression and RKIP expression were observed in 107 cases of gastric cancer through use of tissue microarray technology to identify their correlations with clinicopathological parameters, patient survival, and susceptibility to chemotherapy. The correlation was confirmed in gastric cancer cell lines, analyzed further by gene overexpression and silencing analysis, a cell invasion assay, and a chemosensitivity test. RESULTS: Positive expression of Bmi-1 was highly correlated with T classification and clinical stage. Diminished or lost expression of RKIP was significantly associated with T classification, lymph node metastasis, distant metastasis, and clinical stage. Bmi-1 is negatively and RKIP is positively related to patient survival. Positive expression of Bmi-1 and negative expression of RKIP are associated with poor patient survival and modest efficacy of postoperative chemotherapy. A meaningfully inverse association between Bmi-1 and RKIP was found in tissue microarray studies, and was verified further in gastric cancer cell lines. Moreover, gene overexpression and silencing analysis indicated that RKIP might be regulated by Bmi-1. Furthermore, the impacts of Bmi-1 on cell invasion and chemotherapy resistance were rescued by knockdown of RKIP. CONCLUSIONS: Our study implies that detection of Bmi-1 and RKIP is valuable in predicting patient survival and therapeutic response in gastric cancer, and the inverse association between Bmi-1 and RKIP reveals the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.

Identification and Localization of ß-D-Glucosidase from Two Typical Oenococcus oeni Strains.

ß-D-glucosidase (ßG) gene from Oenococcus oeni SD-2a and 31MBR was cloned, sequenced and analyzed, also intracellular ßG of the two strains was further localized. The results showed that ßG gene of the two strains was in high homology (> 99%) to reported ßG gene, con-firming both strains possess ßG activity at the molecular level. Intracellular ßG of SD-2a is a mainly soluble protein, existing mostly in the cytoplasm and to some extent in the periplasm. While for 31MBR, intracellular ßG is mainly insoluble protein existing in the cytoplasmic membrane. This study provides basic information for further study of the metabolic mechanism of ßG from O. oeni SD-2a and 31MBR.

Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer.

The synergetic inhibitory effects on human pancreatic cancer by nanoparticle-mediated siRNA and arsenic therapy were investigated both in vitro and in vivo. Poly(ethylene glycol)-block-poly(L-lysine) were prepared to form siRNA-complexed polyplex and poly(ethylene glycol)-block-poly(DL-lactide) were prepared to form arsenic-encapsulated vesicle, respectively. Down-regulation of the mutant Kras gene by siRNA caused defective abilities of proliferation, clonal formation, migration, and invasion of pancreatic cancer cells, as well as cell cycle arrest at the G0/G1 phase, which substantially enhanced the apoptosis-inducing effect of arsenic administration. Consequently, co-administration of the two nanomedicines encapsulating siRNA or arsenic showed ideal tumor growth inhibition both in vitro and in vivo as a result of synergistic effect of the siRNA-directed Kras oncogene silencing and arsenic-induced cell apoptosis. These results suggest that the combination of mutant Kras gene silencing and arsenic therapy using nanoparticle-mediated delivery strategy is promising for pancreatic cancer treatment. FROM THE CLINICAL EDITOR: Treatment of pancreatic cancer remains a major challenge. These authors demonstrate a method that combines a siRNA-based Kras silencing with arsenic delivery to pancreatic cancer cells using nanoparticles, resulting in enhanced apoptosis induction in the treated cells.

Glycolysis and tumor progression promoted by the m6A writer VIRMA via m6A-dependent upregulation of STRA6 in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, highlighting the urgent need to elucidate the underlying oncogenic mechanisms. VIRMA is a classic isoform of methyltransferases that participates in epigenetic transcriptomic modification in eukaryotic mRNAs. However, the exact roles of VIRMA in PDAC remain unclear. Here, we identified that VIRMA is highly expressed in PDAC, and histone modifications of the promoter may partly account for this dysregulation. Moreover, VIRMA is closely related to glycolysis and poor prognosis in PDAC. We further determined that STRA6 is a direct downstream target of VIRMA in PDAC by RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq). VIRMA is involved in gene expression regulation via 3' UTR targeting of STRA6 mRNA. Furthermore, the m6A reader IGF2BP2 was shown to critically contribute to the stability of STRA6 mRNA. We describe the role of VIRMA in promoting signaling via the STRA6/STAT3 axis, which results in increased levels of HIF-1α, a key activator of glycolysis. In vivo and in vitro experiments reveal that the VIRMA-STRA6-STAT3-HIF-1α axis plays an instrumental role in glycolysis and tumor progression in PDAC. In conclusion, we demonstrate that VIRMA can increase glycolysis in PDAC by upregulating STRA6, a cell surface membrane protein that stimulates the STAT3 pathway, thereby activating HIF-1α and leading to pancreatic cancer malignancy. Overall, our data strongly suggest that the VIRMA-STRA6-STAT3-HIF-1α axis is a viable therapeutic target in PDAC.

Tumor-associated macrophages drive glycolysis through the IL-8/STAT3/GLUT3 signaling pathway in pancreatic cancer progression.

Glycolytic metabolism is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and tumor-associated stromal cells play important roles in tumor metabolism. We previously reported that tumor-associated macrophages (TAMs) facilitate PDAC progression. However, little is known about whether TAMs are involved in regulating glycolysis in PDAC. Here, we found a positive correlation between CD68+ TAM infiltration and FDG maximal standardized uptake (FDG SUVmax) on PET-CT images of PDAC. We discovered that the glycolytic gene set was prominently enriched in the high TAM infiltration group through Gene Set Enrichment Analysis using The Cancer Genome Atlas database. Mechanistically, TAMs secreted IL-8 to promote GLUT3 expression in PDAC cells, enhancing tumor glycolysis both in vitro and in vivo, whereas this effect could be blocked by the IL-8 receptor inhibitor reparixin. Furthermore, IL-8 promoted the translocation of phosphorylated STAT3 into the nucleus to activate the GLUT3 promoter. Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

Control of postharvest soft rot caused by Erwinia carotovora of vegetables by a strain of Bacillus amyloliquefaciens and its potential modes of action.

Erwinia carotovora subsp. carotovora (Ecc), the causal agent of bacterial soft rot, is one of the destructive pathogens of postharvest vegetables. In this study, a bacterial isolate (BGP20) from the vegetable farm soil showed strong antagonistic activity against Ecc in vitro, and its twofold cell-free culture filtrate showed excellent biocontrol effect in controlling the postharvest bacterial soft rot of potatoes at 25 °C. The anti-Ecc metabolites produced by the isolate BGP20 had a high resistance to high temperature, UV-light and protease K. Based on the colonial morphology, cellular morphology, sporulation, and partial nucleotide sequences of 16S rRNA and gyrB gene, the isolate BGP20 was identified as Bacillus amyloliquefaciens subsp. plantarum. Further in vivo assays showed that the BGP20 cell culture was more effective in controlling the postharvest bacterial soft rot of green peppers and Chinese cabbages than its twofold cell-free culture filtrate. In contrast, the biocontrol effect and safety of the BGP20 cell culture were very poor on potatoes. In the wounds of potatoes treated with both the antagonist BGP20 and the pathogen Ecc, the viable count of Ecc was 31,746 times that of BGP20 at 48 h of incubation at 25 °C. But in the wounds of green peppers, the viable count of BGP20 increased 182.3 times within 48 h, and that of Ecc increased only 51.3 %. In addition, the treatment with both BGP20 and Ecc induced higher activity of phenylalanine ammonia-lyase (PAL) than others in potatoes. But the same treatment did not induce an increase of PAL activity in green peppers. In conclusion, the present study demonstrated that the isolate BGP20 is a promising candidate in biological control of postharvest bacterial soft rot of vegetables, but its main mode of action is different among various vegetables.

Development and validation of a radiomics model of magnetic resonance for predicting liver metastasis in resectable pancreatic ductal adenocarcinoma patients.

BACKGROUND: Nearly one fourth of patients with pancreatic ductal adenocarcinoma (PDAC) occur to liver metastasis after surgery, and liver metastasis is a risk factor for prognosis for those patients with surgery therapy. However, there is no effective way to predict liver metastasis post-operation. METHOD: Clinical data and preoperative magnetic resonance imaging (MRI) of PDAC patients diagnosed between July 2010 and July 2020 were retrospectively collected from three hospital centers in China. The significant MRI radiomics features or clinicopathological characteristics were used to establish a model to predict liver metastasis in the development and validation cohort. RESULTS: A total of 204 PDAC patients from three hospital centers were divided randomly (7:3) into development and validation cohort. Due to poor predictive value of clinical features, MRI radiomics model had similar receiver operating characteristics curve (ROC) value to clinical-radiomics combing model in development cohort (0.878 vs. 0.880, p = 0.897) but better ROC in validation dataset (0.815 vs. 0.732, p = 0.022). Radiomics model got a sensitivity of 0.872/0.750 and a specificity of 0.760/0.822 to predict liver metastasis in development and validation cohort, respectively. Among 54 patients randomly selected with post-operation specimens, fibrosis markers (α-smooth muscle actin) staining was shown to promote radiomics model with ROC value from 0.772 to 0.923 (p = 0.049) to predict liver metastasis. CONCLUSION: This study developed and validated an MRI-based radiomics model and showed a good performance in predicting liver metastasis in resectable PDAC patients.

TIMP1 derived from pancreatic cancer cells stimulates Schwann cells and promotes the occurrence of perineural invasion.

Perineural invasion (PNI) occurs in most pancreatic ductal adenocarcinomas (PDACs). The relationship between cancer cells and peripheral nerves, however, is unknown. Therefore, we focused on the cooperation of PDAC cells and peripheral nerve astrocytes, Schwann cells (SCs), in PNI. The mutual tumor-supportive secretory cytokines between SCs (sNF96.2) and PDAC cells (PANC-1, BxPC-3) were screened by human cytokine arrays and verified. The prognostic value of selected cytokines and SC-associated markers was confirmed in PDAC patients. TIMP1 and CCL7 were found to form a paracrine feedback loop between PDAC cells and SCs. PDAC cell-derived TIMP1 promotes SCs proliferation and migration via CD63/PI3K/AKT signaling. CCL7 secreted from SCs enhances PDAC cell migration, invasion and expression of TIMP1 via CCR2/STAT3. PDAC cell-SC cooperation in PNI was blocked when TIMP1 knockdown in vitro and in vivo. Finally, TIMP1, CCL7 and SC-associated markers were correlated with PNI and prognosis in PDAC patients. In conclusion, SCs collaborate with PDAC cells through the TIMP1-CCL7 paracrine feedback loop to promote PNI. TIMP1 knockdown in PDAC cells suppresses PNI. Strategies to disrupt the TIMP1-CCL7 feedback loop might be developed to inhibit PNI in PDAC.

Arsenic trioxide-loaded nanoparticles enhance the chemosensitivity of gemcitabine in pancreatic cancer via the reversal of pancreatic stellate cell desmoplasia by targeting the AP4/galectin-1 pathway.

Pancreatic stellate cells (PSCs) constitute the fibrotic tumor microenvironment composed of the stroma matrix, which blocks the penetration of gemcitabine (GEM) in pancreatic adenocarcinoma (PDAC) and results in chemoresistance. We analyzed the expression of α-SMA, collagen type I, and fibronectin by immunohistochemistry of pancreatic cancer tissues and demonstrated that the abundant interstitial stroma is associated with dismal survival. Two desmoplastic pancreatic tumor models are treated with arsenic trioxide (ATO) and GEM to confirm the sensitizing effect of ATO on GEM. RNA-seq was performed to analyze the potential fibrotic genes regulated by ATO. Western blotting, CCK-8 methods, colony formation, and wound healing and transwell assays were utilized to verify that ATO attenuates the tumor-promoting ability of PSCs by inhibiting its activation and decreasing matrix secretion via the PI3K/AKT/AP4/galectin-1 pathway. Furthermore, we developed targeted ATO-loaded nanoparticles self-assembled by poly (D,L-lactide) and poly(ethylene glycol) (PEG-PDLLA) and modified by the single-chain antibody of FAP-α (scAbFAP-α) (scAb-ATO-NPs) to promote the delivery efficiency of ATO to PSCs and enhance anti-tumor effects with gemcitabine. Herein, we elucidate the mechanism of how ATO inhibits the activation of PSCs and enhances the therapeutic effect of GEM. We propose a novel cocktail therapy including scAb-ATO-NPs and GEM, indicating a new perspective in the treatment of PDAC.

GLUT1 Regulates the Tumor Immune Microenvironment and Promotes Tumor Metastasis in Pancreatic Adenocarcinoma via ncRNA-mediated Network.

Pancreatic adenocarcinoma (PAAD) is a digestive tumor with extremely high malignancy. Previous studies have reported that Glucose transporter 1 (GLUT1) contributes to the aggressive tumor progression in various cancer types and indicates an unfavorable prognosis. However, the function of GLUT1 in PAAD remains largely unclear. Through pan-cancer analysis of GLUT1 expression, GLUT1 expression was significantly higher in several cancer types including PAAD. Survival analysis based on the GLUT1 expression showed that GLUT1 could serve as a predictor of poor prognosis. We further predicted and screened the candidate non-coding RNAs (ncRNAs) upstream of the GLUT1 mRNA through correlation analysis, and found that the CASC19/miR-140-5p axis contributing to the regulation of GLUT1 expression. Our study suggested a link exists between GLUT1 expression and selected immunity-related indicators. Subsequent analysis revealed overexpression of GLUT1 in pancreatic cancer specimens and patients with highly expressed GLUT1 expression had worse prognosis. Based on the significantly different expression of GLUT1, the possibility that GLUT1 participated in tumor progression was identified. Using online public databases, genes co-expressed with GLUT1 were screened and enriched to metastasis-related pathways by enrichment analysis. Additionally, functional assays verified that GLUT1 could function in the metastatic process of PAAD cancer cells. Therefore, we proposed that GLUT1 might serve as a role in tumor immunity and tumor metastasis, and was expected to be a prognostic factor in PAAD.

A LETM2-Regulated PI3K-Akt Signaling Axis Reveals a Prognostic and Therapeutic Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortalities malignant tumors, which is characterized by difficult diagnosis, rapid progression and high recurrence rate. Nevertheless, PDAC responds poorly to conventional therapies, which highlights the urgency to identify novel prognostic and therapeutic targets. LEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. Thus, this study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in PDAC. In this study, we analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis. The analyses based on the TCGA-GTEx dataset indicated that the LETM2 expression was obviously elevated in several cancers, and it was the most significantly related to the dismal prognosis of PDAC. Subsequently, we demonstrated the functional role and mechanism of LETM2 by clinical sample evaluation, and in in vitro and in vivo experiments. Immunohistochemical analyses showed that high expression of LETM2 was correlated with poor outcomes of PDAC. Moreover, we demonstrated that LETM2 knockdown significantly inhibited tumor proliferation and metastasis, and promoted cell apoptosis, while LETM2 overexpression exerted the opposite effects. Finally, the impairment caused by LETM2-knockdown could be recovered via excitation of the PI3k-Akt pathway in vitro and in vivo animal models, which suggested that LETM2 could activate the downstream PI3K-Akt pathway to participate in PDAC progression. In conclusion, the study enhanced our understanding of LETM2 as an oncogene hallmark of PDAC. LETM2 may facilitate tumor progression by activating the PI3K-Akt signaling pathway, which provides potential targets for the diagnosis, treatment, and prognosis of pancreatic cancer.