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Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing

Bartoschek, Michael LU ; Oskolkov, Nikolay LU ; Bocci, Matteo LU ; Lövrot, John; Larsson, Christer LU ; Sommarin, Mikael LU ; Madsen, Chris LU ; Lindgren, David LU ; Pekar, Gyula and Karlsson, Göran LU , et al. (2018) In Nature Communications
Abstract
Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed... (More)
Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs. (Less)
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@article{c575ec7b-8873-4243-9163-de4f8f58faec,
  abstract     = {Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs.},
  articleno    = {5150},
  author       = {Bartoschek, Michael and Oskolkov, Nikolay and Bocci, Matteo and Lövrot, John and Larsson, Christer and Sommarin, Mikael and Madsen, Chris and Lindgren, David and Pekar, Gyula and Karlsson, Göran and Ringnér, Markus and Bergh, Jonas and Björklund, Åsa K. and Pietras, Kristian},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing},
  url          = {http://dx.doi.org/10.1038/s41467-018-07582-3},
  year         = {2018},
}