The role of serine biosynthesis in breast cancer-derived lung metastasis

Breast cancer is the most frequent type of tumor among women worldwide, accounting for 24.2% of all the tumor cases. Due to these tremendous incidences, breast cancer is also the type of tumor causing the highest number of deaths, indeed around 600.000 women die every year because of this disease. By taking a closer look at the prognosis of patients diagnosed with breast cancer, it appears evident that the progression of the disease towards a metastatic stage reduces the survival rates. Indeed, metastasis formation is the leading cause of death for patients with cancer, including breast cancer. The inefficacy of the current therapies highlights how the metastatic cascade, due to its complexity, is still the least understood process of cancer biology. Thus, we are in urgent need of novel therapeutic strategies and this thesis aims at expanding our understanding of the fundamental biological processes underlying the metastatic process of breast cancer cells to provide insights for the design of new therapies. In particular, we focused in this thesis on the cross-talk between cellular metabolism and signal transduction during metastatic outgrowth. Metabolic rewiring is now recognized as a hallmark of cancer. Specifically, metabolic pathways are highjacked by tumor cells to sustain their biomass production and energetic needs during uncontrolled proliferation. Metastatic cancer cells have been shown to rewire their metabolism during multiple steps of the metastatic cascade such as invasion and survival in the circulation. Yet, how metabolic rewiring sustains the last phase of the metastatic process, the metastatic outgrowth of disseminated cancer cells, is still poorly understood. The nutrient composition of the extracellular environment is one of the main determinants of cellular metabolism. Recent work from our group has shown, in the context of a breast cancer murine model, that the lung nutritional microenvironment, which is a recurrent metastatic site for breast cancer cells, is defined by an increased pyruvate availability compared to the mammary tissue. Functionally, the extracellular presence of pyruvate contributes to a permissive niche for metastatic breast cancer cells that rewire their metabolism to sustain extracellular matrix remodeling. However, the role of a pyruvate rich microenvironment on the metabolism of outgrowing metastases remains elusive. Activation of growth signaling is critical during the last step of metastasis formation. One of the key cell signaling pathways sustaining cellular growth and proliferation is represented by mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that exists in two complexes, namely mTORC1 and mTORC2. mTORC1 represents a central hub that coordinates metabolic signals and cellular functions to ultimately sustain cell growth and proliferation. Given its crucial role, mTORC1 aberrant activation has been found in multiple cancer contributing to uncontrolled proliferation. Yet, it remains largely unknow whether and how mTORC1 signaling is activated in cancer cells that have successfully disseminated to a distant organ. The overarching objective of this thesis was to investigate how nutrient availability impacts cellular metabolism and growth signaling in primary breast cancer cells and their corresponding lung metastasis during the metastatic outgrowth. Mechanistically, we found that pyruvate, a nutrient available in the lung environment, supports the activation of mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production during metastasis formation. Overexpression of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH) stimulated sensitivity to rapamycin in breast cancer-derived lung tumors. Accordingly, while silencing of PHGDH in breast cancer cells abolished sensitivity to rapamycin in lung tumors, it did not change sensitivity towards mTORC1 inhibition in primary breast tumors. In summary, we show that breast cancer cells growing in the lung metastatic niche have different metabolic requirements to activate mTORC1 signaling than the same breast cancer cells growing in the primary tumor site.

Jaar van publicatie:2020

Toegankelijkheid:Open