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Int J Mol Sci. 2019 Sep 9;20(18). pii: E4438. doi: 10.3390/ijms20184438.

Phenotypic Plasticity of Fibroblasts during Mammary Carcinoma Development.

Author information

1
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
2
Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, 60438 Frankfurt, Germany.
3
Institute of Cardiovascular Regeneration, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
4
Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, 61231, Germany.
5
Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany.
6
Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, IME, 60590 Frankfurt, Germany.
7
German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany.
8
Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, 60438 Frankfurt, Germany. kathi.zarnack@bmls.de.
9
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany. weigert@biochem.uni-frankfurt.de.

Abstract

: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.

KEYWORDS:

cancer; cancer-associated fibroblasts; gene signature; mammary carcinoma; transcriptional profiling

Conflict of interest statement

Funding: This research was funded by Deutsche Forschungsgemeinschaft (SFB 1039 TP B04 and B06; FOR 2438), Deutsche Krebshilfe (70112451), and Else Kröner Fresenius-Foundation (Graduate school Translational Research Innovation—Pharma (TRIP) and Else Kröner Fresenius Graduate School). The APC was funded by the ‘Open-Access-Publikationsfonds’ of Goethe-University Frankfurt.

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