Project description
Understanding how metastasising cancer cells create a friendly new environment
Most cancer-related deaths are caused not by the primary tumour but by distant metastasis. During metastasis, cancer cells face the challenges of different microenvironments to which they must adapt – or in which they recruit support. Cancer cells directly interact with both the immune system and stromal cells (connective tissue cells), and it is now clear that the immune system can be reprogrammed by tumour cells to be inactive, ineffective or even supportive of tumours. In addition, the stroma and the immune system interact, contributing to a chronically inflamed pro-tumour microenvironment. The EU-funded project ALTER-brain is identifying altered molecular patterns underlying microenvironment reprogramming, focusing on metastasis in the brain given its increasing incidence and poor prognosis. Outcomes will not only enhance understanding of brain biology but also potentially lead to better outcomes for brain metastases.
Objective
Organ colonization is the most inefficient step of metastasis. However, once a few cancer cells manage to re-initiate their growth in the brain, the initial naïve microenvironment, which was not favouring and even actively limiting the number of potential metastasis initiating cells, is slowly rewired into a different ecosystem with pro-metastatic properties. In this project (ALTER-brain), we will study the biology of microenvironment reprogramming to explore innovative ways of treating metastasis.
Microenvironment reprogramming relies on altered molecular patterns that emerge in specific brain cell types simultaneously to the outgrowth of metastases. Dissecting the biology of these emerging patterns and their functional consequences could provide the basis to prevent metastasis but also to treat advances lesions. A key objective of ALTER-brain is the identification of newly established functional networks among previously non-connected components of the microenvironment that are critical to nurture tumour growth.
This research proposal focuses on metastasis in the brain given its rising incidence, poor therapeutic options and short survival rates upon diagnosis. ALTER-brain will use novel (i.e. spontaneous metastasis) and clinically relevant (i.e. relapse after therapy) experimental mouse models of brain metastasis combined with genetically engineered mice in which we will target specific components of the microenvironment. In addition, we will apply novel lineage tracing technologies to understand the origin and emerging heterogeneity of the reprogrammed microenvironment. Given the clinical relevance of our research, human brain metastasis provided by our clinical network will be used to validate key findings.
ALTER-brain will identify key principles underlying the unknown biology of the brain under a specific pathological pressure that might be translated to other highly prevalent disorders affecting this organ in the future.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
28029 Madrid
Spain