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

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

Wednesday, 09.03.2022

Authors and Affiliations:

Carolina F Ruivo # 1 2 3, Nuno Bastos # 1 2 3, Barbara Adem 1 2 3, Ines Batista 1 2 3, Cecilia Duraes 1 2, Carlos A Melo 4, Stephanie A Castaldo 1 5, Francisco Campos-Laborie 4, Pedro Moutinho-Ribeiro 6 7, Barbara Morão 8, Ana Costa-Pinto 1 2, Soraia Silva 1 2, Hugo Osorio 1 2 6, Sergio Ciordia 9, Jose Luis Costa 1 2 6, David Goodrich 10, Bruno Cavadas 1 2, Luisa Pereira 1 2, Tony Kouzarides 4, Guilherme Macedo 6 7, Rui Maio 8 11 12, Fatima Carneiro 1 2 6 7, Marília Cravo 11 13, Raghu Kalluri 14, Jose Carlos Machado 1 2 6, Sonia A Melo 1 2 6
1i3S Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
2IPATIMUP Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
3ICBAS Instituto de Ciencias Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
4Gurdon Institute, Cambridge, Cambridgeshire, UK.
5Department of Oncology, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
6FMUP Faculty of Medicine University of Porto, Porto, Portugal.
7CHUSJ Centro Hospitalar Universitário de São João, Porto, Portugal.
8Hospital Beatriz Ângelo, Loures, Portugal.
9Proteomics Facility, Spanish National Center for Biotechnology, Madrid, Spain.
10Roswell Park Cancer Institute, Buffalo, New York, USA.
11Hospital da Luz, Lisbon, Portugal.
12NOVA Medical School, Lisbon, Portugal.
13FMUL Faculty of Medicine University of Lisbon, Lisbon, Portugal.
14Cancer Biology, University Texas MD Anderson Cancer Center, Houston, Texas, USA.
#Contributed equally.

 

Abstract:

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 worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.
Conclusion: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

 

Journal: GUT

 

Linkhttps://gut.bmj.com/content/early/2022/01/09/gutjnl-2021-324994