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Summary Report:

The therapeutic options for breast cancer metastasis are very limited and still remain an unmet medical need. Our project describes the oxygen sensing protein prolyl hydroxylase 2 (PHD2) as a potential target to reduce metastasis using a spontaneous model of breast cancer including all clinical relevant stages in breast cancer progression. We identified two underlying mechanisms that explain the reduction in metastasis. First, reduced levels of PHD2 resulted in decreased activation of cancer-associated fibroblasts (CAFs) due to impaired paracrine crosstalk from cancer cells to stromal CAFs via TGF-1β. Subsequently, CAFs reciprocally affect cancer cell invasion by modulating the intra-tumoral extracellular matrix (ECM). Second, low PHD2 levels induced tumor vessel normalization resulting in less cancer cells that escape from the primary tumor to form metastases (see graphical abstract overviewing general concept in annex). Previous reports show controversial effects of PHD2 silencing in cancer cells and did not characterize the role of PHD2 in stromal cells (Kuchnio A et al., Cell Reports, 2015). Our data might offer a therapeutic benefit in preventing or minimizing metastatic disease as PHD2 haplodeficiency decreased metastasis even after tumor onset. Furthermore, a retrospective analysis in two different databases gave evidence of our mechanism identified and revealed that lower PHD2 levels in human breast cancer patient samples correlated with reduced expression of CAF activation markers.

Another observation with potential therapeutic relevance was the activity of fatty acid synthase (FASN) in breast cancer cells and also in endothelial cells (ECs). We identified a new mechanism upon FASN silencing or blockade that resulted in reduced proliferation of ECs and cancer cells. In more detail, the substrate of FASN, malonyl-CoA, accumulates in the presence of low FASN activity and is used for protein malonylation as post-translational modification. Specifically, the kinase mechanistic target of rapamycin (mTOR) was identified to be malonylated upon FASN silencing resulting in reduced protein synthesis and subsequently reduced proliferation. Our data show that malonylation - as poorly characterized post-translational modification - has functional impact on signaling molecules such as mTOR which regulate EC proliferation. This observation clearly demonstrates the close interaction between cellular metabolism and central signaling pathways that might have therapeutic potential to reduce pathological vessel formation in cancer, specifically in breast cancer.
The data described above on FASN in ECs are part of a manuscript that is in final preparation of submission to Molecular Cell (Bruning U et al., Molecular Cell, 2016, final preparation of submission).

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