Colorectal cancer (CRC) belongs to the most frequent tumor entities in both men and women. Although early detection and certain therapies have improved, the prognosis for patients with metastatic diseases is dismal and survival rates are below 10% at 5 years after diagnosis. Colorectal carcinogenesis is greatly dependent on the plasticity of both tumor cells as well as surrounding stromal cells within the tumor microenvironment. Among the latter, both T cells as well as fibroblasts substantially contribute to the survival prognosis. Importantly, fibroblasts are very heterogenous and various subtypes have been recently described in other tumor entities. Most likely these subtypes rather represent different activation states and have the capacity to interconvert, however, their precise functional role is unknown. Thus, a detailed mechanistic understanding about the cancer-stromal cross-talk as well as the stromal plasticity in CRC, particularly during late tumor stages and the relevance for metastasis development is lacking. Here we aim to perform well-defined hypothesis driven approaches to characterize the plasticity of both tumor and stromal cells and to develop innovative tools that will allow the functional analysis of distinct cell types in the stroma of primary tumors as well as in the pre-metastatic niche in the liver. This will be complemented by unbiased in vivo screens to identify novel pathways involved in plasticity of tumor epithelia and hepatocytes contributing to metastasis formation. Collectively, the combination of these comprehensive approaches that are based on sophisticated novel in vivo models as well as functional analysis of patient samples will ultimately aid the development of novel therapeutic strategies for late-stage CRC patients.
