KAFs - Paving The Way For New Cancer Therapies

In recent years the traditional view of cancer as a group of malignantly transformed cells has been greatly revised. The importance of the tumour vasculature, the immune system, the extracellular matrix as well as other cell types of the tumour stroma to promote tumour progression and metastasis have been demonstrated in many experimental studies. However, one cell type, which is in close contact to neoplastic cells throughout tumour progression, the fibroblast, has barely been characterized. Our knowledge of the role of resting and activated fibroblasts in cancer is still evolving, but there is now convincing evidence that the so-called cancer-associated fibroblasts (CAFs) differ from those associated with normal tissue. Only recently CAFs have been shown to play an important role in modulating malignant progression, and are therefore attractive targets for cancer therapy, especially since in contrast to cancer cells, CAFs rarely display genetic mutations. However, the origin of CAFs, their phenotypic and functional heterogeneity remain elusive. Importantly, we have recently demonstrated that skin dermis arises from two distinct fibroblast lineages, which have different functions in homeostasis and during regeneration, and thus, it is very likely that these fibroblast lineages play unique roles during epithelial cancer formation and progression. Therefore, I would like to focus my research on unravelling the mechanism by which cancer cells reprogram normal fibroblasts into cancer-associated fibroblasts, and how CAFs alter the microenvironment to promote tumour growth and metastasis in particular in squamous cell carcinoma of the skin and melanoma, which has a high predilection for metastatic progression with 44-64% of patients developing brain metastasis. By employing in vivo lineage tracing techniques in combination with single cell RNA sequencing I aim to disclose the origin of CAFs and dissect stromal heterogeneity at both molecular and functional levels, and address how different CAF subsets support malignant progression. In conclusion, this study will not only improve our understanding about the role of the tumour stroma and microenvironment during tumour formation and metastasis but will also provide novel targets for anti-tumour therapy, new markers which could be used for drug delivery via immunotherapy, as well as biomarkers for evaluating the metastatic potential of a given tumour, and might also boost the development of personalized cancer treatments. 1

In recent years the traditional view of cancer as a group of malignantly transformed cells has been greatly revised. The importance of the tumor vasculature, the immune system, the extracellular matrix as well as other cell types of the cancer stroma to promote cancer progression and metastasis have been demonstrated in many experimental studies. However, one cell type, which is in close contact to neoplastic cells throughout tumor progression, the fibroblast, has barely been characterized. Only recently the so-called cancer-associated fibroblasts (CAFs) have been shown to play an important role in modulating malignant progression, and are therefore attractive targets for cancer therapy, especially since in contrast to cancer cells, CAFs rarely display genetic mutations. By employing in vivo lineage tracing techniques and various in vitro and in vivo assays in murine skin cancer models in combination with single cell RNA sequencing of human basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and melanoma biopsies, we could show that distinct CAF subsets exist, for which we predict different functions in cancer progression according to their expression profiles. Intriguingly, one CAF subset that is predominant in malignant skin cancer, expresses a variety of immunomodulatory factors, suggesting that these CAFs influence tumor immune surveillance and possibly the response to immunotherapy. In addition, we identified novel biomarkers for these distinct CAF subsets. In conclusion, this study has advanced our understanding about the role of the cancer-associated fibroblasts during tumor progression, and we identified novel biomarkers for diagnostic and prognostic assessment of human skin cancer biopsies as well as potential novel anti-cancer targets. Thus, our findings may boost the development of personalized cancer treatments.