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The main research interest of the Rüegg laboratory is the study of the interactions between the tumor and its host. Growing evidence indicates that carcinogenesis and tumor progression are not simply cell autonomous processes, but rather a condition involving multiple heterotypic multi-cellular interactions between cancer cells and their microenvironment. Hence, the concept of tumor microenvironment as an integrated and essential part of the tumor tissue was coined. Today the tumor microenvironment is considered as a therapeutic target with great potential for new therapeutic approaches. Hence, the interest in unraveling molecular mechanisms of bidirectional communication.

The tumor microenvironment. Tumor cells orchestrate directly (e.g. through the release of factors) or indirectly (though the induction of tissue hypoxia or appearance of necrosis) the modification of the microenvironment by attracting or activating many non-tumoral cells, including blood and lymphatic endothelial cells and pericytes, carcinoma associated fibroblast, bone marrow-derived cells, immune and inflammatory cells. Tumor cells can also deposit or modify the extracellular matrix. Most of these stromal modifications start early during tumor progression, often at the transition stage from premalignant to malignant lesion. In some cases they may even precede cancer formation, for example in situations of chronic inflammation. In turn, tumor microenvironmental events promote tumor progression by stimulating tumor growth and survival, and facilitating invasion and metastasis. Collectively these events will contribute to determine the outcome of tumor progression: tumor growth, tumor dormancy, tumor invasion and metastasis and resistance to therapy (Figure 1).

Tumor adaptation and evasion from therapy. There is growing evidence that therapeutic interventions such as surgery, chemotherapy or bone marrow supportive treatments aimed at counterbalancing toxic effects of chemotherapy, may promote tumor progression. It is therefore possible that anti-cancer therapy when it fails, it may actually push the tumors toward a more aggressive behavior.

We should start considering the possibility that anti-cancer treatment, if not sufficiently effective, may exert additional selective pressure on the tumor cells and the tumor microenvironment resulting in the accelerated appearance cells with increased metastatic capacities.

In the laboratory we are addressing the following questions:

• Tumor microenvironment: How do cells of the microenvironment, in particular bone marrow-derived cells promote tumor progression? How do therapeutic interventions modify the tumor microenvironment and how do these modifications impact tumor behavior?
• Tumor metastasis: How does the cross-talk between tumor cells and the microenvironment evolve during tumor progression toward metastasis? Is there a hierarchy of metastatic cells within the primary tumor, and how can we identify them?
• How do tumors adapt and evade anticancer therapies. How do tumors and the microenvironment react to anticancer therapies, in particular anti-angiogenic therapies, chemotherapy and radiotherapy, and what are the consequences to tumor progression?

Results issued from this program have the potential to give rise to new therapeutic approaches with potential applications to patients. Considering the clinical relevance of the addressed questions, we expect that some of the obtained results will have translational and clinical relevance. They are likely to identify approaches to prevent cancer formation and progression including metastasis formation, for example by impinging on the formation of the pre-metastatic niche. In view of potential clinical applications, the main applicant has extensive experience in translational studies and is well connected with various oncology units in Switzerland and abroad.