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

Abstract

ObjectiveIntratumor 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.DesignWe 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).ResultsWe 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.ConclusionPDAC 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.

Cancer stem cell-derived extracellular vesicles preferentially target MHC-II– macrophages and PD1+ T cells in the tumor microenvironment

“…A recent study used first-degree genetic labeling of tEV-targeted cells and focused on tumor cell-to-tumor cell signaling via EVs. 54 The Authors uncovered an effective cooperation network mediated by tEVs and led by CSC, suggesting that a similar network may be in place between CSC and immune cells. Given the importance of CSC in cancer biology 19 , new technologies that allow to dissect the influence of native tEVs CSC are necessary.…”

Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma

“…Functionally, the EVs have also been demonstrated as key mediators to establish molecular cross-talk between cancer cells and various types of cellular components within the tumor microenvironment (TME) for promoting tumorigenesis by delivering their cargos 38 . EVs have been shown to promote growth, angiogenesis, migration, invasion, and chemoresistance in PDACs 18 , 39 , 40 . Tang et al have demonstrated that exosomes isolated from PDAC patients promote the proliferation, migration, and invasion of MiaPaCa-2 and AsPC-1 cells 41 .…”

“…Indeed, a role of tumor-derived EVs in premetastatic niche formation and immune suppression has been reported in PDAC 49 . In several reports, EV composition has also been studied to understand their roles in disease pathobiology 39 , 50 , 51 . Along the same lines, the presence of both genomic and mtDNA in EVs has also been reported 38 , 52 , 53 .…”

“…www.nature.com/scientificreports/ tumorigenesis by delivering their cargos 38 . EVs have been shown to promote growth, angiogenesis, migration, invasion, and chemoresistance in PDACs 18,39,40 . Tang et al have demonstrated that exosomes isolated from PDAC patients promote the proliferation, migration, and invasion of MiaPaCa-2 and AsPC-1 cells 41 .…”

Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness

“…AGRN has been shown to contribute to EMT in liver and pancreatic cancer [ 90 , 91 , 92 ]. In hepatocellular carcinoma (HCC) cells, AGRN is overexpressed and secreted in high levels compared with non-tumor liver cells.…”