E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

Sommariva, Michele; Gagliano, Nicoletta

doi:10.3390/cells9041040

Cited by 65 publications

(35 citation statements)

References 154 publications

(194 reference statements)

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“…On the other hand, we have shown an important decrease in the expression of the epithelial marker E-cadherin in tumor cells from our co-culture model, suggesting that EMT occurs in this system and would facilitate the initiation of metastasis (4). However, variable expression of E-cadherin in human pancreatic cancer samples and commercial cell lines has been con rmed in several studies, supporting the hypothesis that PDAC cells exhibit a hybrid EMT-related phenotype (38).…”

Section: Discussionsupporting

confidence: 79%

Tumor-Stroma Co-Cultures Modify the Invasive Properties of Human Pancreatic Adenocarcinoma Cells Through Different Patterns of Cytokine Secretion and Depending on the Type of Cell Lines.

Prieto-García¹,

Díaz-García²,

Agudo-López³

et al. 2021

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer worldwide. One key feature of PDAC is a dense desmoplastic reaction that has become recognized to play important roles in tumor growth, metastasis, and therapeutic resistance. We aim to study tumor-stromal interactions in an in vitro co-culture model between human PDAC cells and fibroblasts.Methods: Capan-1 or PL-45 human pancreatic tumor cell lines and LC5 fibroblasts were grown in direct or indirect co-cultures, and their relationship regarding migratory and invasive properties were studied by wound-healing and transwell migration assays. Confocal immunofluorescence, ELISA, and western blotting were used to evaluate the expression of activation markers. Cytokines arrays were performed to identify secretome profiles associated to migratory and invasive properties of tumor cells. Extracellular vesicles production was examined by ELISA and transmission electron microscopy. Results: Co-cultures conditions increased FGF-7 secretion and α-SMA expression, characterizing fibroblasts activation; and decreased epithelial marker E-cadherin in tumor cells, suggesting that they suffer epithelial-to-mesenchymal transition. The expression pattern of cytokine secretion differed under co-culture conditions versus monocultures, with GM-CSF, GRO a/b/g, GRO-α, IL-6, IL-8, MCP-1, and RANTES being the most affected. A greater number of exosomes with higher amount of proteins was quantified in co-cultures assays. Interestingly, tumor cells and fibroblasts migrate as a package, with tumor cells in the middle surrounded by fibroblasts, and maximizing the contact between cell to cell. Conclusions: We show different migratory properties in tumor and stromal cells, and we draw a different mechanism for tumor spread through a cooperative migration between tumor cells and activated fibroblasts. Furthermore, we found that the level of IL-6 mainly, in addition to other cytokines, change significantly in co-cultures conditions with respect to monocultures, and this could affect the invasive and migratory capacities of cells. Targeting the interaction between tumor cells and tumor microenvironment might represent a novel therapeutic approach to advance pancreatic carcinoma.

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Section: Discussionsupporting

confidence: 79%

Tumor-Stroma Co-Cultures Modify the Invasive Properties of Human Pancreatic Adenocarcinoma Cells Through Different Patterns of Cytokine Secretion and Depending on the Type of Cell Lines.

Prieto-García¹,

Díaz-García²,

Agudo-López³

et al. 2021

Preprint

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“…Indeed, vimentin is a marker of mesenchymal features, while ZEB1 represents a transcriptional repressor of epithelial-to-mesenchymal transition (EMT) induction [ 96 , 97 ]. Since E-cadherin deficiency and vimentin/ZEB1 upregulation are associated with EMT mechanisms, it is not surprising that UDC is a particularly aggressive variant [ 98 ].…”

Section: Genetic and Molecular Features Of Pdac Variantsmentioning

confidence: 99%

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Bazzichetto

Luchini

Cognetti

et al. 2020

IJMS

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To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

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“…Tumoral cells are characterized by loss of adherent junctions and thus cell polarity, while gaining migratory and invasive properties, an event known as epithelial-tomesenchymal transition [EMT, (Prieto-Garcia et al, 2017)]. Cadherins dysregulation is part of the EMT (Hanahan and Weinberg, 2011): loss of E-cadherin from the PM is an early indicator of EMT and a marker of poor prognosis in many cancers (Bremnes et al, 2002;Chen et al, 2003;Fan et al, 2019;Sommariva and Gagliano, 2020), making the trafficking of E-cadherin an area of great interest for the discovery of new mechanisms that modulate cell adhesion (Cadwell et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 controls the transport of E-cadherin

Grimaldi

Schembri

et al. 2020

Preprint

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ADP-ribosylation is a post-translational modification involved in physiological and pathological events catalyzed by Poly-ADP-Ribosyl-Polymerase (PARP) enzymes. Substrates of this reaction have been identified by mass-spectrometry, but the definition of PARPs-regulated cellular functions remains scarce. Here, we have analyzed the control of intracellular membrane traffic by the mono-ADP-ribosyl-transferase PARP12, motivated by its localization at the trans-Golgi network. By using bioinformatics, mutagenesis and cell biology approaches we identified Golgin-97, a protein regulating exocytosis, as a PARP12-specific substrate. Mono-ADP-ribosylation of Golgin-97 residues E558-E559-E565 is required for supporting traffic from the trans-Golgi network to the plasma membrane. This step is halted when PARP12 is deleted or when the Golgin-97 ADPribosylation-defective mutant is expressed. Under these conditions E-cadherin, whose transport is controlled by Golgin-97, does not reach the plasma membrane but accumulates in a trans-Golgi proximal compartment. Thus, we demonstrate that the ADP-ribosylation of Golgin-97 is required for E-cadherin exocytosis and thus this event may regulate the sorting of exocytic carriers as well as epithelial-to-mesenchymal transition.

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E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

Cited by 65 publications

References 154 publications

Tumor-Stroma Co-Cultures Modify the Invasive Properties of Human Pancreatic Adenocarcinoma Cells Through Different Patterns of Cytokine Secretion and Depending on the Type of Cell Lines.

Tumor-Stroma Co-Cultures Modify the Invasive Properties of Human Pancreatic Adenocarcinoma Cells Through Different Patterns of Cytokine Secretion and Depending on the Type of Cell Lines.

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 controls the transport of E-cadherin

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