No abstract

Metastases are the leading cause of mortality in patients with cancer. Metastasis formation requires cancer cells to adapt their cellular phenotype. However, how metabolism supports this adaptation of cancer cells is poorly defined. We use 2D versus 3D cultivation to induce a shift in the cellular phenotype of breast cancer cells. We discover that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture. Subsequently, we link proline catabolism to in vivo metastasis formation. In particular, we find that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh is sufficient to impair formation of lung metastases in the orthotopic 4T1 and EMT6.5 mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discover that Prodh is a potential drug target for inhibiting metastasis formation.

Metabolic transformation is a hallmark of cancer and a critical target for cancer therapy. Cancer metabolism and behavior are regulated by cell-intrinsic factors, as well as metabolite availability in the tumor microenvironment (TME). This metabolic niche within the TME is shaped by four tiers of regulation, including: 1) intrinsic tumor cell metabolism, 2) interactions between cancer and non-cancerous cells, 3) tumor location and heterogeneity, and 4) whole-body metabolic homeostasis. Here, we will define these modes of metabolic regulation and review how distinct cell types contribute to the metabolite composition of the TME. Finally, we will connect these insights to understand how each of these tiers offers a unique therapeutic potential to modulate the metabolic profile and function of all cells inhabiting the TME.