The metabolic requirements of breast cancer cells during metastatic colonization

Metastasis formation is the main cause of cancer-associated deaths. This cancer progression process is a cascade consisting of different steps, each characterized by a specific cellular phenotype of the cancer cells. Specifically, cancer cells from the primary tumor invade the surrounding tissue and access the circulatory system to reach distant organs. In the distant organ, cancer cells undergo a period of dormancy and survival before they colonize the organ and build established metastases. When cancer cells change their cellular phenotype during metastasis formation they also need to adapt their metabolism. Yet, the metabolic reprogramming of metastasizing cancer cells is poorly defined. From a clinical point of view, the latter steps of metastasis formation are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already infiltrated, but have not yet colonized a distant organ. When cancer cells transform from an infiltration state i.e. a single cell or cell cluster stage, to a colonization state i.e. a micrometastases stage, they have to remodel the extracellular matrix (ECM) that allows them to gain growth an survival signaling and they have to grow into three dimensional colonies, i.e micrometastases. However, the metabolic requirements for this transformation processes remain understudied. Thus, the objectives of this PhD thesis were to investigated how nutrient metabolism supports the growth of colonizing cancer cells and to which extent ECM remodeling is metabolically regulated. We addressed both objectives on the model system of breast cancer cells and metastasis formation in the lung. First, we investigated how nutrient metabolism supports colonizing breast cancer cells. We discovered that breast cancer cells rely on proline metabolism in order to form colonies. Specifically, we found that the main function of proline utilization was proline dehydrogenase (Prodh) dependent ATP production. Inhibition of Prodh was sufficient to impair colony formation in vitro. Moreover, we found that proline catabolism is increased in vivo in the metastases tissue of patients and mice. Finally, we demonstrated that inhibiting Prodh impaired lung metastasis formation in two orthotopic breast cancer mouse models. Second, we investigated to which extent ECM remodeling by colonizing breast cancer cells is metabolically regulated. We discovered that α-ketoglutarate derived from pyruvate is essential for ECM remodeling during colonization of breast cancer cells. Specifically, we found that α-ketoglutarate metabolically activated prolyl-4-hydroxylase (P4HA), which is the rate-limiting enzyme for the deposition of the ECM component collagen. Strikingly, pyruvate deprivation drastically impaired collagen deposition by colonizing breast cancer cells. Additionally, we have evidence that this metabolic regulation is relevant in vivo for breast cancer derived metastasis formation. Taken together, with this thesis we provide two novel metabolic drug targets that have the potential to prevent metastasis formation. Future studies are needed to translate our findings towards patient benefit.

Publication year:2017

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