Abstract 1003: Improving the functional taxonomy of breast cancer-associated fibroblasts by single-cell RNA sequencing reveals clinically relevant cellular subsets

Aim: The traditional tumor cell-centric view of cancer has been replaced in the past years with the appreciation of the importance of the tumor microenvironment for the malignant phenotype. Cancer-associated fibroblasts (CAFs) are the main constituent of the breast tumor microenvironment, although the exact origin and role of CAF subpopulations in disease initiation, progression and response to treatment remain unclear. Therefore, cancer therapies targeting CAFs are not available. Methods: Here, we delineate the heterogeneity of CAFs through single-cell RNA sequencing of 768 EPCAM-CD31-CD45-NG2- cells from the MMTV-PyMT mouse model of breast cancer. Results and discussion: Unbiased transcriptional clustering and differential gene expression analysis revealed four populations, with functionally distinct transcriptional profiles. The existence of these cell populations was further validated by immunostaining in experimental and human tumors revealing a preferential localization of each CAF subtype within the tumor microenvironment. Gene profiles specific to each CAF subpopulation held prognostic capability in clinical cohorts and correlated to known functional gene profiles. Our high-resolution comparison of single-cell transcriptomes in CAFs reveals previously unappreciated functional diversity within the tumor microenvironment. Conclusions: Ultimately, our delineation of an improved taxonomy of breast CAFs reveals a previously unappreciated functional diversity within the tumor microenvironment and opens the possibility for biomarker-driven development of new drugs for precision medicine. Citation Format: Michael Bartoschek, Kristian Pietras. Improving the functional taxonomy of breast cancer-associated fibroblasts by single-cell RNA sequencing reveals clinically relevant cellular subsets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1003.