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

• DOI: 10.1002/path.5224
• Publication Date: 2018-12-21T16:02:36Z
• Authors: Cindy Neuzillet; Annemilaï Tijeras...; Chanthirika Ragulan; Jérôme Cros; Yatish Patil; Matthieu Martinet; Mert Erkan; Jörg Kleeff; Jeremy Wilson; Minoti Apte; Marie Tosolini; Abigail S Wilson; Francesca R Delve...; Corinne Bousquet; Valérie Paradis; Pascal Hammel; Anguraj Sadanandam; Hemant M Kocher
• Keywords: Cancer-Associated Fibroblasts

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