Phenotypic Plasticity of Fibroblasts during Mammary Carcinoma Development

• Published in: International journal of molecular sciences Vol. 20; no. 18; p. 4438
• Main Authors: Elwakeel, Eiman, Brüggemann, Mirko, Fink, Annika F, Schulz, Marcel H, Schmid, Tobias, Savai, Rajkumar, Brüne, Bernhard, Zarnack, Kathi, Weigert, Andreas
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.09.2019; MDPI
• Subjects: Adipocytes; Animals; Breast cancer; Cancer; cancer-associated fibroblasts; Carcinoma; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene expression; Gene Expression Regulation, Neoplastic; gene signature; Growth factors; Heterogeneity; Homeostasis; mammary carcinoma; Mammary gland; Mammary glands; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Medical prognosis; Metastases; Mice; Mice, Transgenic; Phenotypic plasticity; Population; Smooth muscle; Transcription, Genetic; transcriptional profiling; Tumorigenesis; Tumors; transcriptional profiling; cancer-associated fibroblasts; cancer; gene signature; mammary carcinoma
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20184438

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.