Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

作者：Carolina F. Ruivo, Nuno Bastos, Bárbara Adem, Inês A. Batista, Cecília Durães, Carlos Alberto Melo, Stéphanie A. Castaldo, Francisco Jose Campos-Laborie, Pedro Moutinho-Ribeiro, B Morão, Ana Rita Costa-Pinto, Soraia R. M. R. Silva, Hugo Osório, Sergio Ciordia, José Luís Costa, David W. Goodrich, Bruno Cavadas, Luı́sa Pereira, Tony Kouzarides, Guilherme Macedo, Rui Maio, Fátima Carneiro, Marilia L. Cravo, Raghu K. Kalluri, José Carlos Machado, Sónia A. Melo · 发表于：Gut · 年份：2022 · DOI：10.1136/gutjnl-2021-324994 · 被引用次数：103 · 研究领域：Extracellular vesicles in disease、Cancer Cells and Metastasis、Nanoplatforms for cancer theranostics

Objective Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour. Design We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs). Results We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP. Patients with high levels of agrin and low inactive YAP show ...