In Germany, more than 4 million patients live with the diagnosis cancer . For many of them local disease control could be achieved and they live under the Damocles' sword of pending relapse, i.e. the threat of death from metachronous metastasis. Late distant relapses, however, demonstrate that disseminated cancer cells (DCCs) survive long periods outside the primary tumour and retain the ability to grow and form a metastasis. But what are the mechanisms that are operative during clinical latency periods? What determines whether DCCs remain under control or start to form metastases? Which systemic or organ-specific factors prevent or promote distant relapse after primary treatment and how could therapeutic intervention prevent metachronous metastasis best? The TRR 305 is focusing on these specific questions of the complex metastatic cascade with the goal to pave the way for the development of a new generation of metastasis-preventive therapies. The research programme is structured into two key research areas that reflect the main objectives. Research area A - Cancer cell adaptation to selection forces will focus on cell intrinsic properties functionally linked to the generation of metastasis. It will comprise a framework for the understanding of the sequence of mutational events and thereby define the evolutionary and molecular state of colonising DCCs upon which plasticity is generated. It will then address mechanisms of cancer cell plasticity directly, i.e. how it is generated and how it is regulated. It also includes a technical platform to measure responses of cancer cells to changing microenvironmental conditions and selection forces. Research area B - Immune and niche-dependent conditions of metastatic colonisation focuses on cancer cell interactions with the microenvironment at colony formation. These interactions can either be organ-independent and of general significance or organ-specific determining site-specific metastasis, reflecting the co-adaptation of invading DCCs and niche cells. Also, research area B comprises a technology development project for studying complex cellular interactions by novel in vitro assays. These two research areas built upon each other and thereby will provide ample opportunity and need for interaction and cooperation. Together, they will reciprocally inform about the best and most promising preclinical implementation and enable critical evaluation of clinical targeting chances. These steps will be enabled and promoted by the central Z-platforms.
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