Targeting the Metabolic Dependencies of Metastatic Tumor Cells

Metastasis is responsible for over 90% of deaths that occur in patients with cancer.

So far there are no therapies that precisely target a metastatic disease due to the limited number of efficient druggable targets.Recently, I discovered in melanoma: circulating tumor cells are depending on arginine for their survival. In addition, I revealed that liver metastases specifically upregulate their alanine metabolism during metastasis.

Thus, metastatic cells at different stages have dependencies on unique amino acids (AA).

While most research focuses on the primary stage, my proposal will focus on the missing gap aiming to prevent metastases formation.

Based on these new paradigm-changing discoveries, I hypothesize that metastatic cells modulate their AA metabolism during metastatic progression, and targeting the unique AA dependencies will decrease their survival and metastatic potential.

Using sophisticated in vivo metastasis assays both in mouse and in patient, cutting-edge mass spectrometry and in vivo isotope tracing technologies, I will identify metastasis-specific inhibitors by investigating the following questions. I. How does arginine support melanoma cell survival in circulation?

By using metabolomics, stable isotope tracer analysis and transplantation assays both in mouse and human, I will uncover how we can use this unique AA dependency of CTCs as a novel target. II.How does metabolic heterogeneity in the circulating tumor cells support organotropism?

To mechanically dissect metastatic organotropism, I will map metabolic differences in melanoma metastases and also examine how we can target alanine metabolism to block metastases. The understanding of AA adaptation of cancer cells is essential for the prevention of metastasis.

My results will reveal new metabolic pathways that are required by metastasizing cells in vivo and therefore will fundamentally advance the ability to develop new targeted therapies for preventing early and late-stage metastatic cancer.