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

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Busch, SusannGothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology (author)

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

Article/chapterEnglish2017

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2017-04-03
Springer Science and Business Media LLC,2017

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LIBRIS-ID:oai:gup.ub.gu.se/253648
https://gup.ub.gu.se/publication/253648URI
https://doi.org/10.1186/s12943-017-0642-7DOI

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Language:English

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Subject category:art swepub-publicationtype

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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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
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

Added entries (persons, corporate bodies, meetings, titles ...)

Andersson, Daniel,1979Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology(Swepub:gu)xadanw (author)
Bom, EvaGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xdifev (author)
Walsh, Claire,1983Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology(Swepub:gu)xwalcl (author)
Ståhlberg, Anders,1975Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology(Swepub:gu)xsandw (author)
Landberg, Göran,1963Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology(Swepub:gu)xlgora (author)
Göteborgs universitetSahlgrenska Cancer Center (creator_code:org_t)

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In:Molecular Cancer: Springer Science and Business Media LLC16:11476-4598

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