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Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.

ABSTRACT: Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from ?- or ?-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted ?- and ?-cells. To confirm cell identity, we investigate ARX and PDX1 expression. Based on epigenetic similarities, PanNETs cluster in ?-like, ?-like and intermediate tumours. The epigenetic similarity to ?-cells progressively decreases in the intermediate tumours, which present unclear differentiation. Specific transcription factor methylation and expression vary in the respective ?/?-tumour groups. Depending on DNAme similarity to ?/?-cells, PanNETs have different mutational spectra, stage of the disease and prognosis, indicating potential means of PanNET progression.

SUBMITTER: Di Domenico A

PROVIDER: S-EPMC7721725 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.

Di Domenico Annunziata A Pipinikas Christodoulos P CP Maire Renaud S RS Bräutigam Konstantin K Simillion Cedric C Dettmer Matthias S MS Vassella Erik E Thirlwell Chrissie C Perren Aurel A Marinoni Ilaria I

Communications biology 20201207 1

Recent data suggest that Pancreatic Neuroendocrine Tumours (PanNETs) originate from α- or β-cells of the islets of Langerhans. The majority of PanNETs are non-functional and do not express cell-type specific hormones. In the current study we examine whether tumour DNA methylation (DNAme) profiling combined with genomic data is able to identify cell of origin and to reveal pathways involved in PanNET progression. We analyse genome-wide DNAme data of 125 PanNETs and sorted α- and β-cells. To confi ...[more]

PMID: 33288854

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Project description:Non-tumoural cells within the tumour microenvironment (TME) influence tumour proliferation, invasiveness and angiogenesis. Little is known about TME in pituitary neuroendocrine tumours (PitNETs). We aimed to characterise the role of TME in the aggressive behaviour of PitNETs, focusing on immune cells and cytokines. The cytokine secretome of 16 clinically non-functioning PitNETs (NF-PitNETs) and 8 somatotropinomas was assessed in primary culture using an immunoassay panel with 42 cytokines. This was correlated with macrophage (CD68, HLA-DR, CD163), T-lymphocyte (CD8, CD4, FOXP3), B-lymphocyte (CD20), neutrophil (neutrophil elastase) and endothelial cells (CD31) content, compared to normal pituitaries (NPs, n?=?5). In vitro tumour-macrophage interactions were assessed by conditioned medium (CM) of GH3 (pituitary tumour) and RAW264.7 (macrophage) cell lines on morphology, migration/invasion, epithelial-to-mesenchymal transition and cytokine secretion. IL-8, CCL2, CCL3, CCL4, CXCL10, CCL22 and CXCL1 are the main PitNET-derived cytokines. PitNETs with increased macrophage and neutrophil content had higher IL-8, CCL2, CCL3, CCL4 and CXCL1 levels. CD8+ T-lymphocytes were associated to higher CCL2, CCL4 and VEGF-A levels. PitNETs had more macrophages than NPs (p?<?0.001), with a 3-fold increased CD163:HLA-DR macrophage ratio. PitNETs contained more CD4+ T-lymphocytes (p?=?0.005), but fewer neutrophils (p?=?0.047) with a 2-fold decreased CD8:CD4 ratio. NF-PitNETs secreted more cytokines and had 9 times more neutrophils than somatotropinomas (p?=?0.002). PitNETs with higher Ki-67 had more FOXP3+ T cells, as well as lower CD68:FOXP3, CD8:CD4 and CD8:FOXP3 ratios. PitNETs with "deleterious immune phenotype" (CD68hiCD4hiFOXP3hiCD20hi) had a Ki-67???3%. CD163:HLA-DR macrophage ratio was positively correlated with microvessel density (p?=?0.015) and area (p?<?0.001). GH3 cell-CM increased macrophage chemotaxis, while macrophage-CM changed morphology, invasion, epithelial-to-mesenchymal transition and secreted cytokines of GH3 cells. PitNETs are characterised by increased CD163:HLA-DR macrophage and reduced CD8:CD4 and CD8:FOXP3 T cell ratios. PitNET-derived chemokines facilitate macrophage, neutrophil and T cell recruitment into the tumours which can determine aggressive behaviour.

Dataset Information

Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.

Publications

Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression.

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