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

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.

CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer

“…Generally speaking, the term 'cancer-associated fibroblast' is used to describe all activated fibroblastic cells in the TME of solid cancers that have a phenotype, function, or location distinct from normal, quiescent fibroblasts. It is thought that the most frequent cellular precursor for pancreatic CAFs are PSCs [30,31]. PSCs can be identified by the expression of desmin and glial fibrillary acidic protein (GFAP), as well as acetylcholine receptors and vitamin A-containing lipid droplets, all of which are distinct from other fibroblast populations [32][33][34], but share similarities with other stellate cells throughout the body, such as hepatic stellate cells [34,35].…”

“…Cancer Cell Genotype-Driven CAF Heterogeneity PDAC tumours are molecularly heterogeneous; different regions of the tumour contain molecularly distinct cancer cells, which results in distinct CAF subpopulations ( Figure 1B) [24][25][26]31,[48][49][50][51]. Laklai et al (2016) revealed that the genetically regulated phenotype of pancreatic tumour cells tunes the function of the adjacent periductal stroma to promote tumourigenesis via integrin and Yes-associated protein (YAP) signalling [7].…”

Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection

“…Pancreatic cancer is characterized by an abundant desmoplastic stroma, dominated by cancer‐associated fibroblasts (CAFs), which play an important role in the biological behaviour of cancer cells. Recently, high heterogeneity among CAFs has been reported, but their precise role and clinical significance remain to be established.…”

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

“…However, PDGFRα seems to be a prominent CAF marker in skin cancer (Arwert et al, 2012;Erez et al, 2010) and recently PDGFRα was suggested as a pan-CAF marker in pancreatic cancer as it was detected in all 4 transcriptomically defined CAF subpopulations (Neuzillet et al, 2019). In a follow-up study of pancreatic cancer, RNA-sequencing discovered that PDPN was a widely expressed CAF marker, and PDGFRα only present on a subpopulation of the CAFs (Elyada et al, 2019).…”