Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK

Masi, Ilenia; Caprara, Valentina; Spadaro, Francesca; Chellini, Lidia; Sestito, Rosanna; Zancla, Andrea; Rainer, Alberto; Bagnato, Anna; Rosanò, Laura

doi:10.1016/j.celrep.2021.108800

Cited by 18 publications

(25 citation statements)

References 80 publications

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“…In addition, we found ILK expression was significantly associated with metastases of clinical specimens. And the association between ILK and cell survival and deterioration of ovarian cancer has also been reported before [ 63 – 67 ]. Although it has been demonstrated that the transcription of SNAIL1 can be regulated by ILK protein in certain cancers [ 52 , 53 ].…”

Section: Discussionsupporting

confidence: 61%

Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer

Yuan

Ruan

et al. 2022

Cell Death Dis

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Partitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial–mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin β1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin β1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.

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Section: Discussionsupporting

confidence: 61%

Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer

Yuan

Ruan

et al. 2022

Cell Death Dis

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“…We previously demonstrated that the ET-1/ET A R axis in SOC cells facilitates adhesion and transmesothelial migration ( Masi et al, 2021a ). To investigate whether ET-1-induced MMT conversion might impact the transmesothelial migration of SOC cells, we used a co-culture system using fluorescent-labelled OVCAR3 cells and MCs previously cultured with or without ET-1 and/or BQ123 and BQ788.…”

Section: Resultsmentioning

confidence: 99%

“…An active ET-1 axis, involving the interaction with ET A R and ET B R, supports SOC growth and progression, and key signaling pathways activated by ET-1 related to invasion and metastasis are orchestrated by the cooperation of protein β-arrestins (β-arrs) with signaling proteins in cytosolic or nuclear compartments ( Rosanò et al, 2013 ; Peterson and Luttrell, 2017 ; Bagnato and Rosanò 2019 ; Tocci et al, 2019 ). Our recent studies addressing the question of how the ET-1 axis contributes to the reorganization of the cytoskeleton and cell motility during SOC metastatic progression uncovered a relevant role in invadopodia, F-actin-based protrusive membrane structures operating focused matrix degradation ( Masi et al, 2021a ). Acting as an anchoring point for players and signaling molecules regulating cell adhesion, invasion and proteolysis, β-arr1 determines the convergence of specific signal transducers ( Semprucci et al, 2016 ; Di Modugno et al, 2018 ; Chellini et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis

Rio

Masi

Caprara

et al. 2021

Front. Cell Dev. Biol.

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Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Here we investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes in MCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associated with the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependent MAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NF-kB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETBR or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC pro-metastatic behaviour via MMT.

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“…S4A, B). Given that previous evidence describing the ability of ILK to promote YAP nuclear translocation [ 35 ] and because we have previously pointed out that ILK is downstream to the ET-1 signaling to promote OC cell invasive behaviour [ 7 , 9 , 36 ], we then investigated the involvement of this kinase in mediating the ET-1-induced YAP activity. IB analyses confirmed the capacity of ET-1/ET A R axis to upregulate ILK that was curbed by macitentan pre-treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional interaction between endothelin-1 and ZEB1/YAP signaling regulates cellular plasticity and metastasis in high-grade serous ovarian cancer

Sestito

Tocci

Roman

et al. 2022

J Exp Clin Cancer Res

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Background Epithelial-to-mesenchymal transition (EMT) encompasses a highly dynamic and complex key process which leads to metastatic progression. In high-grade serous ovarian carcinoma (HG-SOC), endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling promotes EMT driving tumor progression. However, the complex nature of intertwined regulatory circuits activated by ET-1 to trigger the metastatic process is not fully elucidated. Methods The capacity of ET-1 pathway to guide a critical transcriptional network that is instrumental for metastatic growth was identified in patient-derived HG-SOC cells and cell lines through immunoblotting, q-RT-PCR, co-immunoprecipitation, in situ proximity ligation, luciferase reporter, chromatin immunoprecipitation assays and publicly available databases. Functional assays in HG-SOC cells and HG-SOC xenografts served to test the inhibitory effects of ET-1 receptors (ET-1R) antagonist in vitro and in vivo. Results We demonstrated that ET-1/ETAR axis promoted the direct physical ZEB1/YAP interaction by inducing their nuclear accumulation in HG-SOC cells. Moreover, ET-1 directed their engagement in a functional transcriptional complex with the potent oncogenic AP-1 factor JUN. This led to the aberrant activation of common target genes, including EDN1 (ET-1) gene, thereby creating a feed-forward loop that sustained a persistent ET-1/ZEB1 signaling activity. Notably, ET-1-induced Integrin-linked kinase (ILK) signaling mediated the activation of YAP/ZEB1 circuit driving cellular plasticity, invasion and EMT. Of therapeutic interest, treatment of HG-SOC cells with the FDA approved ET-1R antagonist macitentan, targeting YAP and ZEB1-driven signaling, suppressed metastasis in vivo in mice. High gene expression of ETAR/ILK/YAP/AP-1/ZEB1 was a strong predictor of poor clinical outcome in serous ovarian cancer patients, indicating the translational relevance of this signature expression. Conclusions This study provides novel mechanistic insights of the ET-1R-driven mediators that support the ability of HG-SOC to acquire metastatic traits which include the cooperation of YAP and ZEB1 regulatory circuit paving the way for innovative treatment of metastatic ovarian cancer.

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Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK

Cited by 18 publications

References 80 publications

Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer

Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial–mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis

Functional interaction between endothelin-1 and ZEB1/YAP signaling regulates cellular plasticity and metastasis in high-grade serous ovarian cancer

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