Deciphering CCL2 signalling in/via the extracellular matrix

The signalling molecule CCL2 is an important player in cancer pathology, in which it promotes cancer progression and metastasis. CCL2 is secreted by tumor, stromal and immune cells and exerts its effect via binding to the receptor CCR2 on target cells. At present knowledge about interactions with other molecules present in the tumor microenvironment, such as molecules of the surrounding scaffold, the extracellular matrix (ECM), is sparse. Up to now, targeting of soluble CCL2 has not been successful and potential interactions of CCL2 with molecules of the ECM might provide the missing link. The hypothesis of the underlying study is that interactions of CCL2 with ECM molecules are important for its biological effects in cancer pathology. These interactions could lead to immobilization, presentation or structural activation of CCL2, which could further have an impact on its signalling properties and therefore on cancer progression. To investigate this hypothesis we will use tumor cell-secreted ECM and analyze with which components CCL2 can interact, how strong these interactions are and if a complexes of more than two interaction partners are involved. Most importantly, we will also investigate the effects of these interactions on tumor cells, T-cells and myeloid-derived suppressor cells, as they are pivotal players in tumor progression. Therefore, we will analyze cell proliferation, adhesion, migration, differentiation and effector molecule secretion - functions that are crucial for promoting tumor progression. In this study we will, for the first time, not only focus on the interaction of CCL2 with its receptor CCR2, but will perform a comprehensive study with the surrounding molecules of the ECM. Moreover, we will also take complexes of more than two molecules into account. Apart from providing us with a better knowledge about CCL2 signalling in cancer and the involvement of the ECM in CCL2 signalling, this study has wide implications for therapeutically targeting CCL2 in cancer progression.

Deciphering CCL2 signalling in/via the extracellular matrix The small, soluble signalling molecule CCL2 is an important player in cancer pathology, where it promotes cancer growth and spread. CCL2 is secreted by tumor-, connective tissue- and immune cells. Molecules like CCL2 rely on interactions with other molecules in the tumor microenvironment including components of the extracellular matrix (ECM). These interactions are needed for CCL2 immobilization and activation. However, knowledge about which molecules CCL2 binds to, and how this impacts its signalling properties and cancer progression, is sparse. In this study we showed for the first time that CCL2 can bind to the ECM molecule tenascin-C (TNC). TNC does not merely function as a scaffold with the matrix, tumor-derived TNC is also involved in the progression of cancer. Therefore, the functions of TNC and CCL2 are overlapping. On top of the interaction between TNC and CCL2, we could also show a correlation in their expression in the context of breast cancer: removing tumor derived TNC reduced the amount of CCL2 secreted by tumor cells. Using the database "The Cancer Genome Atlas" we could also show that there is a correlation of TNC and CCL2 expression in Her2-positive cancer patients, suggesting a clinical relevance. Finally, we investigated the functions of CCL2 and TNC in a mouse model of breast cancer. We found that tumor-derived TNC is dominating the effects on cancer growth and on immune cell function within the tumor, whereas CCL2 is an accessory to the crime. Apart from providing us with a better knowledge about CCL2 and TNC signaling in the cancer microenvironment, this study has implications for therapeutically targeting breast cancer. Up to now, targeting of soluble CCL2 has not been successful and potential interactions of CCL2 with molecules of the ECM might provide the missing link.