CICCI · Chemokine functions in collective cancer cell invasion: induction, guidance and systemic dissemination

Chemokine functions in collective cancer cell invasion: induction, guidance and systemic dissemination.

Overview: Collective cancer invasion is a primary invasion mode in many epithelial and mesenchymal cancers, similar to collective movements observed during morphogenesis. Despite its abundance, the molecular regulation of collective invasion processes is poorly understood. The aim of this project was to identify and validate the contribution of chemokines and chemokine receptors to initiate and maintain collective cancer invasion in vitro and in vivo. Objectives: 1) To identify the key chemokine / receptor candidates involed in 3D collective cancer invasion in vitro. 2) Interfere with key chemokine pathways that direct collective invasion using in vitro models. 3) To validate the role of chemokine receptors in collective cancer invasion in vivo in using mouse and zebrafish models. Approach: Expression profiling of chemokines, receptors and growth factors in 3D matrix cultures, 3D invasion cultures and interference studies, in situ immunolabeling, and validation in zebrafish embryos and mouse models. Results: Collectively migrating fibrosarcoma and squamous cell carcinoma (SCC) cells from head and neck tumors were assessed for their chemokine, receptor and growth factor expression using a customized QPCR array. Candidates were identified as matching receptor – ligand pairs and pursued functionally in organotypic cell culture models, using spheroid invasion models and inhibition strategies. Ongoing experiments address the role of candidates in mouse models of cancer invasion and metastasis. As in vivo model for validation of cancer invasion patterns and mechanisms, a zebrafish embryo model using tumor cell implantation was established and validated. The injection location, resulting invasion type and efficiency, and the end-point of invasion were monitored. The data show poor reproducibility of invasion trajectories and pattern, poor compatibility between physiological temperatures of the host organism and the injected human tumour cells. These disadvantages discourage zebrafish embryos for tumor cell invasion studies due to poor reliabiliy and uncontrollable toxicity. Relevance: The identified pathways identify a key regulator of collective invasion in vitro, with validation in vivo, will provide significant insight into the regulation of this process and applicability for therapeutic targeting.

Data: CORDIS, © European Union