Cancer growth and invasion involves the destruction of the normal tissue and extracellular matrix and replacement with tumor tissue. This degradation process is also believed to facilitate the metastatic spread. Solid tumors consist of malignant cancer cells in constant interaction with different types of non-malignant cells termed stromal cells. Still, however, the exact role of the stromal part of the tumor for cancer progression and for the associated extracellular matrix degradation is not well established.
Macrophages constitute a large part of the stromal cells and it has become evident that tumor-infiltrating macrophages have a strong impact on cancer progression. This has led to the suggestion that therapeutic targeting of these cells could form the basis of a powerful new type of cancer treatment. However, there is a strong need for increased understanding of the function of these tumor-associated macrophages in order to optimize the development of such new therapy. Most importantly, different subtypes of macrophages exist, but how these subtypes affect cancer progression and metastasis is very incompletely understood.
In this proposed project, we aim to elucidate the exact role of macrophages belonging to the M2-macrophage subtype for cancer progression and for the accompanying extracellular matrix degradation. By generating novel transgenic mice, we will be able to specifically deplete tumors of M2-macrophages. Combining these mice with state-of-the-art techniques such as two-photon microscopy and next-generation sequencing will provide unique insight about the importance of these stromal cells for the individual steps of cancer progression including initiation, proliferation, angiogenesis, invasion, and metastasis.
Within the last decade, cancer immunotherapy has proven to be a very powerful treatment option for different types of cancer. Still, however, a significant fraction of the treated patients show no or only partial response to the treatment. Local immunosuppression mediated by stromal cells is considered one of the main obstacles to the development of more efficient cancer immunotherapy and specifically M2-macrophages have been suggested to inhibit the anti-cancer immune response. In this project, we will directly study the immunosuppressive function of tumor-associated M2-macrophages in vitro and in vivo using pre-clinical mouse cancer models.
The outlined studies will add significantly to our knowledge about macrophages in cancer biology and aid in the development of new and improved cancer therapy strategies.