Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Siret, Carole; Dobric, Aurélie; Martirosyan, Anna; Terciolo, Chloé; Germain, Sébastien; Bonier, Renaté; Dirami, Thassadite; Dusetti, Nelson; Tomasini, Richard; Rubis, Marion; García, Stéphane; Iovanna, Juan; Lagadic‐Gossmann, Dominique; Rigot, Véronique; André, Frédéric

doi:10.1038/bjc.2017.411

Cited by 20 publications

(33 citation statements)

References 43 publications

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“…This finding confirmed the hypothesis that cadherin subtype switching is not a general characteristic in PDAC, and that in the EMT-related phenotype both cadherins can be expressed. Both E-and P-cadherin mRNA level were detected at the same time in a high number of human samples, confirming that PDAC can exhibit a hybrid EMT-related phenotype [87].…”

Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 59%

“…A recent interesting study analyzed cadherin expression during carcinogenesis from Pancreatic Intraepithelial Neoplasia 1 (PanIN-1) to PDAC. Although a small decrease in the staining intensity was observed between PanIN-2 and PDAC, E-cadherin was found at the sites of cell-cell contacts and remained associated with the cell membrane [87].…”

Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 87%

“…In fact, vitro studies demonstrated that P-cadherin induces pancreatic tumor cell motility and invasiveness [88,89]. P-cadherin resulted in being expressed in the cytoplasm of healthy human pancreas, while progressively increasing at the plasma membrane during carcinogenesis starting from PanIN-1 to PDAC [87]. A coexpression and colocalization of E-cadherin and P-cadherin were observed at the cell membrane.…”

Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 99%

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

Sommariva

Gagliano

2020

Cells

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Epithelial-to-mesenchymal transition (EMT) is a step-wise process observed in normal and tumor cells leading to a switch from epithelial to mesenchymal phenotype. In tumors, EMT provides cancer cells with a metastatic phenotype characterized by E-cadherin down-regulation, cytoskeleton reorganization, motile and invasive potential. E-cadherin down-regulation is known as a key event during EMT. However, E-cadherin expression can be influenced by the different experimental settings and environmental stimuli so that the paradigm of EMT based on the loss of E-cadherin determining tumor cell behavior and fate often becomes an open question. In this review, we aimed at focusing on some critical points in order to improve the knowledge of the dynamic role of epithelial cells plasticity in EMT and, specifically, address the role of E-cadherin as a marker for the EMT axis.

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Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 59%

Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 87%

Section: Emt-related Phenotypes and Hybrid Phenotypesmentioning

confidence: 99%

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

Sommariva

Gagliano

2020

Cells

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“…Pancreatic ductal adenocarcinoma (PDAC) as a highly metastatic with poor prognosis cancer (20, 21) is an useful model to clarify the impact of E-cadherin on tumour progression. Indeed, it is now recognized that PDAC encompass a range of E/M hybrid cells, reflecting epithelial-mesenchymal plasticity (8, 22–24). Moreover, some PDAC cells with high E-cadherin expression at the cell boundaries exhibit highly invasive and malignant behaviour15.…”

Section: Introductionmentioning

confidence: 99%

E-cadherin is a structuring component of invadopodia in pancreatic cancer

Dobric

Germain

Bonier

et al. 2020

Preprint

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Invasion/metastasis axis is the major driver of cancer mortality. By maintaining tissue cohesion, E-cadherin is considered as a protective marker for tumoral progression. However, recent studies suggested that the appearance of hybrid epithelial-mesenchymal (E/M) cells still expressing E-cadherin is favourable for the establishment of metastasis. This hypothesis is consistent with the observation that most pancreatic ductal adenocarcinomas (PDAC) are invasive and express E-cadherin in primary tumour and metastases. By using a data constituted by a series of patient-derived xenografts (PDX) from the PaCaOmics multi-centric clinical trial, we show that E-cadherin expression is not associated with stages of the pathology, prognosis, and overall survival in PDAC. The role of E-cadherin in PDAC aggressiveness was tested both in vitro and in cancer cell implantation models. We show that E-cadherin is a key component of membrane protrusions implicated in the extracellular matrix remodelling and degradation, called invadopodia. E-cadherin downregulation in a pancreatic model of E/M hybrid cells reveals that E-cadherin downregulates Arp2/3 complex expression. As this complex is essential for branched actin structure, E-cadherin depletion strongly impaired invadopodia formation. On the other hand, we demonstrate that E-cadherin interacts with the membrane protease MT1-MMP at the in-vadopodial membrane. E-cadherin could be recycled back to the invadopodial membrane simultaneously with MT1-MMP. Indeed, both Rab7 vesicle-dependant and/or a Rab11 vesicle-dependant pathway are required for both E-cadherin and MT1-MMP trafficking. This new localization of E-cadherin and its implication in cell invasion shines a new light on hybrid EMT features in tumoral invasion.

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“…P-cadherin is a classical cadherin family protein. Its overexpression in some cancer tissues has been reported [7][8][9][10][11] , and promotes metastasis and proliferation [13][14][15][16][17][18] . As formation of cell aggregates blocks anoikis 8 , and Pcadherin-mediated signaling is important for cancer cell survival 17 , inhibition of P-cadherin function is a potential anticancer strategy.…”

Section: Introductionmentioning

confidence: 99%

On-rate modulation of cadherin interactions by chemical fragments

Senoo

Itô

Nagatoishi

et al. 2020

Preprint

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Many cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the on-rate of X dimerization. Our findings will impact on a strategy for kinetic regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.

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Cadherin-1 and cadherin-3 cooperation determines the aggressiveness of pancreatic ductal adenocarcinoma

Abstract: Our results show differential, but complementary, roles for cadherins during PDAC carcinogenesis and illustrate how their expression conditions the PDAC aggressiveness.

Cited by 20 publications

References 43 publications

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

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

E-cadherin is a structuring component of invadopodia in pancreatic cancer

On-rate modulation of cadherin interactions by chemical fragments

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