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Breast cancer is by far the most frequent gynaecological cancer. Despite considerable advances in antitumor therapies during the last 15 years, metastatic and recurrent breast cancer is still incurable, indicating that the underlying pathogenesis of the disease remains insufficiently characterized. Accumulating evidence suggests that in addition to tumor cell-intrinsic factors, mammary tumorigenesis is steered by non-transformed cells in the tumor microenvironment, which foster disease progression through various mechanisms including structural support, provision of growth and other oncogenic factors, as well as immune shutdown. In breast cancer, fibroblastic stromal cells most likely play a major role in these processes because they are highly abundant in both primary tumors and secondary sites, such as lymph nodes (LNs) and bone metastases. In addition, stromal cell gene signatures show predictive value regarding breast cancer survival and/or treatment response. However, a comprehensive investigation of different cell subsets that constitute the non-transformed cell compartment in breast cancer is lacking. More importantly, it remains unclear whether particular breast tumor-infiltrating fibroblasts can function as therapeutic targets. Our group has developed model systems to target distinct fibroblastic stromal cell subsets. Recent results from these studies indicate that interleukin-7 (IL-7) expression marks a particular fibroblastic stromal cell type that critically impacts mammary cancer development and progression.

The major aim of this project is to determine the nature of IL-7 expressing breast CAFs in primary tumors and in LN metastases. To achieve a comprehensive analysis of these cells in the tumor microenvironment, we will utilize the latest cell sorting techniques to purify the cells using mouse models that facilitate specific labelling of breast CAFs based on Cre-mediated recombination. Moreover, complementary in-depth analyses and sorting routines will be developed to define corresponding stromal cell subsets from human surgical breast tumor specimens. First, we will trace and isolate IL-7 producing CAFs from both primary (Aim 1) and LN-metastatic breast cancer lesions (Aim 2) to comparatively characterize mesenchymal tumor stromal cells from different anatomical sites using flow cytometry, confocal microscopy and mRNA expression analysis. These studies on murine breast cancer will be complemented by a thorough characterization of human breast CAFs isolated from fresh surgical specimens, again from the primary tumor and LN metastases (Aim 3). Lastly, we will perform an innovative cross species comparison of CAF gene expression signatures to decipher shared regulatory circuits of breast tumor growth in primary and LN-metastatic sites, and to assess a possible association with functional IL-7 expression (Aim 4).