Periodic Reporting for period 1 - META2 (METAbolism of bone METAstasis (META2): Metabolic interactions between disseminated breast cancer cells and osteoblast lineage cells drive bone metastases formation)
Berichtszeitraum: 2019-06-01 bis 2021-05-31
Breast cancer often metastasize to the bone, resulting in progressive bone destruction and severe complications for the patient. Cancer cells colonize the bone already much earlier, but they often stay dormant for several years and remain undetectable. Recent studies showed that at this early stage, cancer cells are in close proximity to bone-forming cells (osteoblasts), and this interaction promotes their survival and proliferation. Interestingly, recent findings also indicate that the way tumor cells use nutrient – cell metabolism - not only drives primary tumor growth, but also determines which cells will metastasize to lung or liver, indicating metabolic interactions of cells with their microenvironment. This concept may also apply to breast cancer in bone, but insight in the metabolism of cells colonizing the bone is lacking. I hypothesize that to survive and thrive in the bone cells rely on a specific profile that is complementary in nutrient needs to osteoblasts. Thus, my objective is to characterize the metabolism of breast cancer cells in bone at early time points and to validate that targeting this metabolism will limit or prevent bone metastasis. To this end, I will combine metabolomics and transcriptomics on in vivo and in vitro models to identify important metabolic enzymes that will then be validated in in vivo models and human samples. This better understanding of the metabolism of cancer cells in the bone is essential for the development of new diagnostic tools and therapeutic targets.
As a first step, I studied cell metabolism of breast cancer in the bone using preclinical mouse models and in vitro cell culture. From the study of bone metastasis transcriptome, as well as from metabolite measurement in their microenvironment, I generated a dataset of metabolic alteration occurring during bone metastasis. As a second parallel step, I studied the metabolism of cell cultures of breast cancer cells and bone cells. By combining the results of these 2 approaches, I selected the four most altered metabolic enzymes in bone metastasis. I then performed genetic or pharmacologic inhibition of these four candidates, and found that one of them was important for bone metastasis formation. These results could lead to new drug development or repositioning of existing drugs for bone metastasis treatment. The important dataset that I generated can be used by others to identify more candidates for bone metastasis, increasing therapeutic opportunities for bone metastasis patients
META2 project allowed us to perform the first detailed analysis of metabolism of bone metastasis. Increasing studies focus on metabolism, as this is a promising therapeutic target for cancer, but data on bone metastasis were lacking. Our project will allow to have a better insight on which nutrient are used by which cells in the bone metastasis environment. This is crucial for the development of safer and more efficient therapies for bone metastasis.