A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion

Malacrida, Beatrice; Nichols, Sam; Maniati, Eleni; Jones, Roanne R.; Delanie-Smith, Robin; Roozitalab, Reza; Tyler, Eleanor J.; Thomas, Morgan; Boot, Gina; Mackerodt, Jonas; Lockley, Michelle; Knight, Martin M.; Balkwill, Frances R.; Pearce, Oliver M.T.

doi:10.1016/j.isci.2021.102676

Cited by 35 publications

(26 citation statements)

References 34 publications

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“…As our understanding of the biology of ovarian TME is evolving, new therapeutic strategies by interrupting tumor/MC bidirectional signaling are emerging. Very powerful studies deconstructing and then reconstructing high-grade SOC omental metastasis, to develop multicellular 3D models and dissect the role of cancer/stroma interaction in early stages of metastatic disease, further confirmed that MCs become activated similarly to malignant cells and a significantly high expression of genes related to mesenchymal transformation is upregulated in malignant cells and MCs (Pearce et al, 2018;Malacrida et al, 2021). On the other hand, cancer-associated MCs might influence in a paracrine manner SOC cell motility not only through secreted soluble factors but also by modifying the stromal ECM, highlighting the importance of targeting MCs to inhibit malignant cell invasion and metastasis (Iwanicki et al, 2011;Davidowitz et al, 2014;Natarajan et al, 2019).…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…There is a large body of evidence that platelets play a profound role in ovarian cancer growth and progression [ 37 ]. Previous findings demonstrated that platelets are present and active in the ascites of patients with ovarian cancer [ 19 , 38 ]. A recent study analysed the platelet content of fresh blood and ascites.…”

Section: Discussionmentioning

confidence: 99%

“…A study by Saha et al recently described an ovarian tumour microenvironment chip that enabled imaging of the complex interaction between the ovarian cancer cells and blood platelets and the resulting metastatic process [ 18 ]. In another work, a multi-cellular model based on HGSOC cell lines enabled the investigation of platelets’ role in malignant cell invasion and ECM production [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Platelet Activation in Ovarian Cancer Ascites: Assessment of GPIIb/IIIa and PF4 in Small Extracellular Vesicles by Nano-Flow Cytometry Analysis

Bortot

Mangogna

Peacock³

et al. 2022

Cancers

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In ovarian cancer, ascites represent the microenvironment in which the platelets extravasate to play their role in the disease progression. We aimed to develop an assay to measure ascites’ platelet activation. We enriched small extracellular vesicles (EVs) (40–200 nm) from ascites of high-grade epithelial ovarian cancer patients (n = 12) using precipitation with polyethylene glycol, and we conducted single-particle phenotyping analysis by nano-flow cytometry after labelling and ultra-centrifugation. Atomic force microscopy single-particle nanomechanical analysis showed heterogeneous distributions in the size of the precipitated particles and their mechanical stiffness. Samples were fluorescently labelled with antibodies specific to the platelet markers GPIIb/IIIa and PF4, showing 2.6 to 18.16% of all particles stained positive for the biomarkers and, simultaneously, the EV membrane labelling. Single-particle phenotyping analysis allowed us to quantify the total number of non-EV particles, the number of small-EVs and the number of platelet-derived small-EVs, providing a platelet activation assessment independent of the ascites volume. The percentage of platelet-derived small-EVs was positively correlated with platelet distribution width to platelet count in sera (PDW/PLT). Overall, we presented a high-throughput method that can be helpful in future studies to determine the correlation between the extent of platelet activation in ascites and disease status.

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“…This protocol is optimized for building 3D models of high-grade serous ovarian cancer omental metastasis but can be adapted for modeling other cancers. For complete details on the use and execution of this profile, please refer to Delaine-Smith et al (2021) and Malacrida et al (2021) .…”

mentioning

confidence: 99%

“…For complete details on the use and execution of this profile, please refer to Delaine-Smith et al (2021) and Malacrida et al (2021) .…”

mentioning

confidence: 99%

Building in vitro 3D human multicellular models of high-grade serous ovarian cancer

2022

Self Cite

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Summary Three-dimensional (3D), multicellular in vitro models provide a useful platform for studying human cancer biology, particularly through deconvolution of the tumor microenvironment, or where animal models do not recapitulate the human condition. Here, we detail a protocol for building human multicellular models made of patient-derived primary cells and malignant cell lines, which recapitulate features of the tumor microenvironment. This protocol is optimized for building 3D models of high-grade serous ovarian cancer omental metastasis but can be adapted for modeling other cancers. For complete details on the use and execution of this profile, please refer to Delaine-Smith et al. (2021) and Malacrida et al. (2021) .

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A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion

Cited by 35 publications

References 34 publications

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

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

Platelet Activation in Ovarian Cancer Ascites: Assessment of GPIIb/IIIa and PF4 in Small Extracellular Vesicles by Nano-Flow Cytometry Analysis

Building in vitro 3D human multicellular models of high-grade serous ovarian cancer

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