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Cellular organization and molecular differentiation model of breast cancer-associated fibroblasts

Journal article
Authors Susann Busch
Daniel Andersson
Eva Bom
Claire Walsh
Anders Ståhlberg
Göran Landberg
Published in Molecular Cancer
Volume 16
Issue 1
ISSN 1476-4598
Publication year 2017
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Language en
Links doi.org/10.1186/s12943-017-0642-7
Keywords Cancer-associated fibroblast, Breast cancer, Tumour stroma, Single-cell analysis, anoikis-resistant phenotype, mesenchymal stem-cells, stromal, myofibroblasts, expression, carcinoma, microenvironment, identification, progression, metastasis, tissue
Subject categories Cancer and Oncology

Abstract

Background: The role of cancer-associated fibroblasts (CAFs) during tumour progression is obscured by the inherently complex, heterotypic nature of fibroblast cells and behaviours in various subtypes of malignancies. Therefore, we sought to identify distinct fibroblast subpopulations at the single-cell level. Methods: Using single-cell quantitative PCR as a powerful tool to study heterogeneity and rare cell events, in a high-throughput manner a panel of gene targets are run simultaneously on transcripts isolated from single cells obtained by fluorescence-activated cell sort. Assessment of cells with stem-like characteristics was attained by anchorage-independent, anoikis-resistant culture. Results: Single-cell analysis of fibroblasts and their tumour-activated counterparts demonstrated molecularly distinct cell types defined by differential expression of characteristic mesenchymal and fibroblast activation markers. Identified subpopulations presented overlapping gene expression patterns indicating transitional molecular states during fibroblast differentiation. Using single-cell resolution data we generated a molecular differentiation model which enabled the classification of patient-derived fibroblasts, validating our modelling approach. Remarkably, a subset of fibroblasts displayed expression of pluripotency markers, which was enriched for in non-adherent conditions. Yet the ability to form single-cell derived spheres was generally reduced in CAFs and upon fibroblast activation through TGF beta 1 ligand and cancer cell-secreted factors. Hence, our data imply the existence of putative stem/progenitor cells as a physiological feature of undifferentiated fibroblasts. Conclusions: Within this comprehensive study we have identified distinct and intersecting molecular profiles defining fibroblast activation states and propose that underlying cellular heterogeneity, fibroblasts are hierarchically organized. Understanding the molecular make-up of cellular organization and differentiation routes will facilitate the discovery of more specific markers for stromal subtypes and targets for anti-stromal therapies.

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