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J Pathol. 2019 May;248(1):51-65. doi: 10.1002/path.5224. Epub 2019 Feb 22.

Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.

Author information

1
Centre for Tumour Biology, Barts Cancer Institute - a CRUK Centre of Excellence, Queen Mary University of London, London, UK.
2
Barts and The London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK.
3
INSERM UMR1149, Beaujon University Hospital, Paris 7 Diderot University, Paris, France.
4
Department of Medical Oncology, Curie Institute, Versailles Saint-Quentin University, Paris, France.
5
AFR Oncology, Paris, France.
6
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
7
Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
8
Department of Pathology, Beaujon University Hospital, Paris 7 Diderot University, Paris, France.
9
Department of Surgery, Koc University School of Medicine, Istanbul, Turkey.
10
Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
11
Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales and Ingham Institute for Applied Medical Research, Sydney, Australia.
12
INSERM UMR 1037, Technological Pole and Bioinformatic Platform, Cancer Research Center of Toulouse, Toulouse, France.
13
INSERM UMR 1037, Team 6 Protein Synthesis and Secretion in Carcinogenesis, Cancer Research Center of Toulouse, Toulouse, France.
14
Digestive Oncology Unit, Beaujon University Hospital, Paris 7 Diderot University, Paris, France.

Abstract

Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

KEYWORDS:

pancreatic stellate cell; stroma; transcriptomics; tumour microenvironment; tumour-stroma interactions

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