Malacrida Beatrice, Nichols Sam, Maniati Eleni, Jones Roanne, 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
Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
School of Engineering and Materials Science, Queen Mary University of London, Mile End, London E1 4NS, UK.
iScience. 2021 May 29;24(6):102676. doi: 10.1016/j.isci.2021.102676. eCollection 2021 Jun 25.
Guided by a multi-level "deconstruction" of omental metastases, we developed a tetra (four cell)-culture model of primary human mesothelial cells, fibroblasts, adipocytes, and high-grade serous ovarian cancer (HGSOC) cell lines. This multi-cellular model replicated key elements of human metastases and allowed malignant cell invasion into the artificial omental structure. Prompted by findings in patient biopsies, we used the model to investigate the role of platelets in malignant cell invasion and extracellular matrix, ECM, production. RNA (sequencing and quantitative polymerase-chain reaction), protein (proteomics and immunohistochemistry) and image analysis revealed that platelets stimulated malignant cell invasion and production of ECM molecules associated with poor prognosis. Moreover, we found that platelet activation of mesothelial cells was critical in stimulating malignant cell invasion. Whilst platelets likely activate both malignant cells and mesothelial cells, the tetra-culture model allowed us to dissect the role of both cell types and model the early stages of HGSOC metastases.
在对网膜转移进行多层次“解构”的指导下，我们建立了一个由原代人间皮细胞、成纤维细胞、脂肪细胞和高级别浆液性卵巢癌（HGSOC）细胞系组成的四细胞培养模型。这个多细胞模型复制了人类转移的关键要素，并使恶性细胞能够侵入人工网膜结构。受患者活检结果的启发，我们使用该模型研究血小板在恶性细胞侵袭和细胞外基质（ECM）产生中的作用。RNA（测序和定量聚合酶链反应）、蛋白质（蛋白质组学和免疫组织化学）和图像分析表明，血小板刺激了恶性细胞侵袭以及与预后不良相关的ECM分子的产生。此外，我们发现血小板对间皮细胞的激活在刺激恶性细胞侵袭中至关重要。虽然血小板可能同时激活恶性细胞和间皮细胞，但四细胞培养模型使我们能够剖析这两种细胞类型的作用，并模拟HGSOC转移的早期阶段。
