Gene Co-expression Network Characterizing Microenvironmental Heterogeneity and Intercellular Communication in Pancreatic Ductal Adenocarcinoma: Implications of Prognostic Significance and Therapeutic Target

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by intensive stroma involvement and heterogeneity. Pancreatic cancer cells interplay with surrounding tumor micro-environment (TME), leading to exacerbated tumorigenesis, dismal prognosis and tenacious therapy resistance. Herein, we aim to ascertain a gene-network indicative of vicious features of TME, then find a vulnerability for pancreatic cancer. Methods Single cell RNA sequencing data was processed by Seurat package, retrieving the cell component marker genes (CCMGs). Correlation networks/modules of CCMGs were determined by WGCNA algorithm in a combined PDAC mRNA expression dataset. The gene modules that statistically associate with prognosis were chosen for classifying TME subgroups, constructing neural network and designing the risk score system. Cell-cell communication analysis was achieved by NATMI software. The tumor suppressive effect of ITGA2 inhibitor was evaluated in vivo by using a Kras G12D -driven murine pancreatic cancer model.Results WGCNA analysis categorized cell component marker genes into eight co-expression networks. From gene modules with the maximum and minimum hazard ratio, we stratify PDAC samples based on TME gene patterns, resulting in two main TME subclasses with contrasting survival periods. Furthermore, we generated a neural network model and a risk score model which robustly predict prognosis and therapeutic outcomes. The hub genes in both gene modules were also gathered for functional enrichment analysis, elucidating a crucial role of cell communication-mediating integrins in TME associated PDAC malignancy. To perform a confirmatory experiment underpinning the significance of hub gene targeting, the mice with spontaneously developed pancreatic cancer were orally treated with an integrin inhibitor. The in vivo assays unraveled that pharmacologically inhibiting ITGA2 counteracts cancer-promoting micro-environment, and ameliorates pancreatic lesions. Conclusions By recapitulating gene-network across various cell types, we exploited novel PDAC prognosis-predicting strategies. Medically interfering ITGA2, a key factor guiding cellular reciprocal interaction, attenuated tumor development. These findings may open new avenue about PDAC targeting therapy.

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KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

BioMed Research International ◽

10.1155/2021/8249293 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jing Chen ◽

Cui-Cui Zhao ◽

Fei-Ran Chen ◽

Guo-Wei Feng ◽

Fei Luo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Disease Free Survival ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth

Neoplasia ◽

10.1016/j.neo.2017.11.007 ◽

2018 ◽

Vol 20 (2) ◽

pp. 152-164 ◽

Cited By ~ 7

Author(s):

Anupama Pal ◽

Michele Dziubinski ◽

Marina Pasca Di Magliano ◽

Diane M. Simeone ◽

Scott Owens ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma

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CD248(TEM1/CD164L1/Endosialin): A new molecular target for anti-angiogenic therapy in Pancreatic ductal adenocarcinoma

10.21203/rs.3.rs-217476/v1 ◽

2021 ◽

Author(s):

Huan Zhang ◽

Zhujiang Dai ◽

Yiqun Liao ◽

Cheng Yan ◽

Bin Zhao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Gene Network ◽

Mirna Gene ◽

Molecular Targets ◽

Diagnosis And Treatment ◽

Ductal Adenocarcinoma ◽

Angiogenic Therapy

Abstract Background: Pancreatic ductal adenocarcinoma (PDCA) is one of the malignant tumors with the worst prognosis with a 5-year survival rate of <1%, which is known as the "king of cancers". At present, there is a lack of effective early diagnosis and treatment plan for pancreatic cancer. Therefore, there is an urgent need to understand the molecular mechanisms of pancreatic cancer to generate innovative approaches for the development of effective early diagnosis and treatment strategies.Methods: In this study, we performed single gene pan-cancer analysis, gene co-expression analysis and gene regulatory correlation analysis to understand the molecular mechanism of CD248 in pancreatic cancer using bioinformatics tools. Additionally, we provided potential molecular targets for pancreatic cancer treatment by constructing the lncRNA-miRNA-gene network axis.Results: The results showed that CD248 is differentially expressed in normal and tumor tissues, and abnormally high expression predicts poor prognosis, is a proto-oncogene in pancreatic cancer. Besides, CD248 is associated with angiogenesis of tumors. We obtained three new lncRNA-miRNA-gene network axes, namely AC008040.1-hsa-miR-200c-3p-CD248 axis, AC055822.1-hsa-miR-200c-3p-CD248 axis, RRN3P2-hsa-miR-200c-3p-CD248 axis that provide promising molecular targets for anti-angiogenic therapy and diagnostic biomarkers for pancreatic cancer.Conclusion: In conclusion, this study shows that over-expression of CD248 (TEM1/CD164L1/Endosialin) is always present in breast cancer and predicts a poor prognosis, associated with tumor angiogenesis, suggesting it as an attractive therapeutic target for pancreatic cancer.

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Rapid diagnosis and tumor margin assessment during pancreatic cancer surgery with the MasSpec Pen technology

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104411118 ◽

2021 ◽

Vol 118 (28) ◽

pp. e2104411118

Author(s):

Mary E. King ◽

Jialing Zhang ◽

John Q. Lin ◽

Kyana Y. Garza ◽

Rachel J. DeHoog ◽

...

Keyword(s):

Pancreatic Cancer ◽

Bile Duct ◽

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Frozen Section ◽

Cancer Surgery ◽

Ductal Adenocarcinoma ◽

Tumor Margins ◽

Histologic Heterogeneity

Intraoperative delineation of tumor margins is critical for effective pancreatic cancer surgery. Yet, intraoperative frozen section analysis of tumor margins is a time-consuming and often challenging procedure that can yield confounding results due to histologic heterogeneity and tissue-processing artifacts. We have previously described the development of the MasSpec Pen technology as a handheld mass spectrometry–based device for nondestructive tissue analysis. Here, we evaluated the usefulness of the MasSpec Pen for intraoperative diagnosis of pancreatic ductal adenocarcinoma based on alterations in the metabolite and lipid profiles in in vivo and ex vivo tissues. We used the MasSpec Pen to analyze 157 banked human tissues, including pancreatic ductal adenocarcinoma, pancreatic, and bile duct tissues. Classification models generated from the molecular data yielded an overall agreement with pathology of 91.5%, sensitivity of 95.5%, and specificity of 89.7% for discriminating normal pancreas from cancer. We built a second classifier to distinguish bile duct from pancreatic cancer, achieving an overall accuracy of 95%, sensitivity of 92%, and specificity of 100%. We then translated the MasSpec Pen to the operative room and predicted on in vivo and ex vivo data acquired during 18 pancreatic surgeries, achieving 93.8% overall agreement with final postoperative pathology reports. Notably, when integrating banked tissue data with intraoperative data, an improved agreement of 100% was achieved. The result obtained demonstrate that the MasSpec Pen provides high predictive performance for tissue diagnosis and compatibility for intraoperative use, suggesting that the technology may be useful to guide surgical decision-making during pancreatic cancer surgeries.

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TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.628353 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jianyou Gu ◽

Wenjie Huang ◽

Junfeng Zhang ◽

Xianxing Wang ◽

Tian Tao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Cellular Proliferation ◽

Function Analysis ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Discovering key transcriptomic regulators in pancreatic ductal adenocarcinoma using Dirichlet process Gaussian mixture model

Scientific Reports ◽

10.1038/s41598-021-87234-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sk Md Mosaddek Hossain ◽

Aanzil Akram Halsana ◽

Lutfunnesa Khatun ◽

Sumanta Ray ◽

Anirban Mukhopadhyay

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Mixture Model ◽

Cancer Progression ◽

Dirichlet Process ◽

Network Inference ◽

Correlation Method ◽

Gaussian Mixture ◽

Ductal Adenocarcinoma ◽

Gene Regulatory Network Inference ◽

Gene Modules

AbstractPancreatic Ductal Adenocarcinoma (PDAC) is the most lethal type of pancreatic cancer, late detection leading to its therapeutic failure. This study aims to determine the key regulatory genes and their impacts on the disease’s progression, helping the disease’s etiology, which is still mostly unknown. We leverage the landmark advantages of time-series gene expression data of this disease and thereby identified the key regulators that capture the characteristics of gene activity patterns in the cancer progression. We have identified the key gene modules and predicted the functions of top genes from a reconstructed gene association network (GAN). A variation of the partial correlation method is utilized to analyze the GAN, followed by a gene function prediction task. Moreover, we have identified regulators for each target gene by gene regulatory network inference using the dynamical GENIE3 (dynGENIE3) algorithm. The Dirichlet process Gaussian process mixture model and cubic spline regression model (splineTimeR) are employed to identify the key gene modules and differentially expressed genes, respectively. Our analysis demonstrates a panel of key regulators and gene modules that are crucial for PDAC disease progression.

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NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Feng Guo ◽

Yingke Zhou ◽

Hui Guo ◽

Dianyun Ren ◽

Xin Jin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Transcriptional Activation ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Gene Sets ◽

And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

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Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00138.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. G524-G536 ◽

Cited By ~ 12

Author(s):

Sandrina Maertin ◽

Jason M. Elperin ◽

Ethan Lotshaw ◽

Matthias Sendler ◽

Steven D. Speakman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Oxidative Phosphorylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Environmental Stresses ◽

Ductal Adenocarcinoma ◽

Cell Adaptation ◽

Autophagy Inhibition ◽

Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

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