TY  - JOUR
A1  - Elwakeel, Eiman
A1  - Brüggemann, Mirko
A1  - Fink, Annika F.
A1  - Schulz, Marcel Holger
A1  - Schmid, Tobias
A1  - Savai, Rajkumar
A1  - Brüne, Bernhard
A1  - Zarnack, Katharina
A1  - Weigert, Andreas
T1  - Phenotypic plasticity of fibroblasts during mammary carcinoma development
T2  - International journal of molecular sciences
N2  - 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.
KW  - cancer-associated fibroblasts
KW  - mammary carcinoma
KW  - cancer
KW  - transcriptional profiling
KW  - gene signature
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51994
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-519949
SN  - 1422-0067
SN  - 1661-6596
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
VL  - 20
IS  - 18, Art. 4438
SP  - 1
EP  - 23
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -