Abstract 3714: Role of miR-29a in pancreatic stellate cell mediated stromal remodeling in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Shatovisha Dey ◽  
Sheng Liu ◽  
Tricia D. Factora ◽  
Solaema Taleb ◽  
Primavera Riverahernandez ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Stellate Cell ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Stellate Cell

scholarly journals Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

2020 ◽  
Author(s):  
Shatovisha Dey ◽  
Sheng Liu ◽  
Tricia D Factora ◽  
Solaema Taleb ◽  
Primavera Riverahernandez ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Stellate Cell ◽  
Critical Role ◽  
Differentially Expressed ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Stellate Cell ◽  
Western Blots ◽  
Incidence And Mortality

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. MethodsIn this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. ResultsRNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. ConclusionsTogether, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.

scholarly journals Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

2020 ◽  
Author(s):  
Shatovisha Dey ◽  
Sheng Liu ◽  
Tricia D Factora ◽  
Solaema Taleb ◽  
Primavera Riverahernandez ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Stellate Cell ◽  
Critical Role ◽  
Differentially Expressed ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Stellate Cell ◽  
Western Blots ◽  
Incidence And Mortality

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. Methods In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. Results RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. Conclusions Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.

scholarly journals Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

2020 ◽  
Author(s):  
Shatovisha Dey ◽  
Sheng Liu ◽  
Tricia D Factora ◽  
Solaema Taleb ◽  
Primavera Riverahernandez ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Stellate Cell ◽  
Critical Role ◽  
Differentially Expressed ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Stellate Cell ◽  
Western Blots ◽  
Incidence And Mortality

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. Methods In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing hPSC cells and controls. Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top candidate miR-29a targets in hPSC cells transfected with miR-29a mimic or scramble control. Results RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. Conclusions Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-tumor cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.

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

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.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

scholarly journals Pancreatic ductal adenocarcinoma concomitant with pancreatic metastases of clear-cell renal cell carcinoma: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Lena Haeberle ◽  
Melanie Busch ◽  
Julian Kirchner ◽  
Georg Fluegen ◽  
Gerald Antoch ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Ductal Adenocarcinoma ◽  
Special Role ◽  
Cell Renal Cell Carcinoma ◽  
Pancreatic Metastases

Abstract Background Metastatic spread to the pancreas is a rare event. Renal cell carcinoma represents one possible site of origin of pancreatic metastases. Renal cell carcinoma often metastasizes late and exclusively to the pancreas, suggesting a special role of renal cell carcinoma among primaries metastasizing to the pancreas. Even rarer, renal cell carcinoma may occur simultaneously with pancreatic ductal adenocarcinoma. Case presentation We present the case of a 78-year-old male Caucasian patient with a history of clear-cell renal cell carcinoma treated with oncological left nephrectomy 20 years before. The patient was diagnosed with pancreatic ductal adenocarcinoma by fine-needle aspiration cytology. At our institution, he received neoadjuvant therapy with folic acid, fluorouracil, irinotecan, oxaliplatin for borderline-resectable pancreatic ductal adenocarcinoma, and subsequently underwent total pancreatectomy. Upon resection, pancreatic ductal adenocarcinoma as well as two metachronous metastases of clear-cell renal cell carcinoma occurring simultaneously and cospatially with pancreatic ductal adenocarcinoma were diagnosed in the pancreatic body. Conclusions Renal cell carcinoma metastases of the pancreas are rare and often occur decades after the initial diagnosis of renal cell carcinoma. The combination of renal cell carcinoma metastases and pancreatic ductal adenocarcinoma is even rarer. However, the possibility should be considered by clinicians, radiologists, and pathologists. The special role of renal cell carcinoma as a site of origin of pancreatic metastasis should be further elucidated.

scholarly journals The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment

2020 ◽  
Vol 19 ◽  
pp. 153303382092096
Author(s):  
Hongzhi Sun ◽  
Bo Zhang ◽  
Haijun Li
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Stromal Cells ◽  
Genomic Analysis ◽  
Ductal Adenocarcinoma ◽  
Genetic Mutations ◽  
Cellular Processes ◽  
Dismal Prognosis ◽  
Mutant Genes

Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

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