Exploring functional subsets of cancer-associated fibroblasts
Abstract: The tumor microenvironment consists of several interacting cell types. Cancer research focssed mainly on the malignant cell in the past. The importance of the tumor microenvironment is increasingly appreciated, as endothelial cells and immune cells were identified as targets for anti-tumor therapy. Targeted therapy against cancer-associated fibroblasts (CAFs) are not in clinical use for the treatment of carcinomas, even though CAFs are involved in many tumor-supporting processes. CAFs are mesenchymal stromal cells and generate and modulate the extracellular matrix (ECM), which provides physical stability to the growing tumor. CAFs can alter cell-to-cell communication within the tumor microenvironment and thereby influence the immune reaction to cancer cells, the response to cancer therapy and the tumor metabolism.Breast cancer is the most common malignant disease and second most common reason for cancer-related death in women. Despite advancements in the treatment of breast cancer, some aggressive forms remain hard to treat.In the first paper we investigated the effect of complement oligomeric matrix protein (COMP) on breast cancer. Epithelial COMP expression is associated with reduced survival in breast cancer patients.We showed that COMP resolves endoplasmic reticulum stress and deregulates the cell metabolism, causing increased growth and metastasis in vivo. We propose COMP expression as a potential prognostic marker in breast cancer.In the second part of the thesis we analyzed the importance of platelet-derived growth factor (PDGF) signaling in solid tumors in general, and the effect of PDGF-CC signaling in breast cancer in particular. We showed that PDGF-CC signaling to CAFs and the subsequent release of CAF-derived stanniocalcin 1, hepatocyte growth factor, and insulin growth factor binding protein 3 maintain a basal-like phenotype in breast cancer. Genetic and pharmacologic disruption of this commuication loop resulted in conversion of a hormone receptor-negative into a hormone receptor-positive state, causing enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that the breast cancer subtype is in part under the control of the tumor microenvironment.CAFs have many different functions in the tumor microenvironment and different origins for CAFs have been suggested. In the last paper we used single-cell RNA-sequencing of 786 mesenchymal cells derived from tumors of the MMTV-PyMT mouse model of breast cancer, to identify subclasses of CAFs in an unbiased approach. We detected and confirmed the existence of four subclasses that potentially derive from three different origins. Based on differential gene expression analysis we assigned functional properties to each CAF subgroup. Gene profiles of the main CAF subgroups held independent prognostic capability in large clinical cohorts. We showed that an in depth investigation of cellular constituents of the tumor microenvironment with increased resolution, can reveal a higher order of cellular organization in malignant disease.
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