CICCI

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

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 Obiettivo del progetto (Objective)

'Cancer progression recapitulates, in part, ill-fated morphogenesis, including single-cell and collective cell migration and associated invasive growth, metastasis and poor prognosis of cancer disease. Chemokines and their receptors enhance cancer progression, by supporting both cancer invasion and proliferation. Previous studies have addressed chemokine function on individual cancer cell functions with emphasis on in vitro effects, yet their contribution to in vivo growth and collective cancer invasion remain unclear. In this project, using state-of the art in vitro and in vivo models, the impact of chemokines and chemokine receptor expression and function on collective cancer invasion and leader-cell function will be addressed. Candidate chemokines identified through in vitro invasion studies will be tested for their ability to guide collective cancer invasion in vivo, using orthotopic 3D matrix cultures and down modulation or overexpression of individual or multiple chemokine receptors. Chemokine-driven collective invasion will be monitored in orthotopic tumor xenografts in nude mice or zebrafish embryos, monitored by intravital microscopy. By inhibiting and/or overexpressing defined chemokine receptor pairs, chemokine-mediated cell sorting and leader-cell function will be monitored. This project will show new functions of chemokine signaling in collective cancer cell invasion, in reminiscence of multicellular movements during embryonic development.'

Introduzione (Teaser)

Cancer represents one of the leading causes of mortality worldwide. Efforts to delineate the mechanisms implicated in cancer onset and progression will have important socioeconomic consequences.

Descrizione progetto (Article)

In many aspects, cancer biology has many features resembling developmental processes such as cell migration. Invasion represents a fundamental step in tumour progression and is the main driving force for metastasis and cancer-related mortality. Accumulating evidence indicates that similar to the early stages in development, cancer cells of many epithelial and mesenchymal tumours also invade in a collective manner.

The detailed mechanisms and molecular determinants of this collective invasion model are poorly understood. To shed light into this phenomenon, the EU-funded CICCI project investigated the role of chemokines and their receptors. Chemokines are small signalling proteins usually implicated in immune responses that also enhance cancer progression. However, the majority of existing data on the role of chemokines has been obtained at the single cell level. Researchers wished to extend these findings in vivo in mouse and zebrafish models.

To this end, they performed extensive expression analysis in fibrosarcoma and squamous cell carcinoma cells from head and neck tumours in three-dimensional invasion cultures. Key chemokine molecules and their receptors were identified and validated through in vitro inhibition or overexpression experiments. Additionally, orthotopic tumour xenografts in nude mice were performed to evaluate the role of chemokines in vivo.

Overall, the CICCI project provided vital information on the role of chemokines on collective cancer invasion in vivo. Understanding the mechanisms that drive cancer cell metastasis could unveil potential therapeutic targets against cancer.