Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Polysomal RNA-Seq)
Lung metastases are detected in more than half of patients with metastatic tumors. However, it remains largely unknown why the lung environment is a permissive niche for metastases. Here, we discover that pulmonary aspartate triggers a cellular signaling cascade in disseminated cancer cells resulting in a translational program that boosts lung metastasis. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-D-aspartate (NMDA) receptor in cancer cells, which induces CREB-dependent mRNA expression of deoxyhypusine hydroxylase (DOHH). The latter is essential for hypusination, a posttranslational modification required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational program with TGF-ß signaling as a central hub promotes collagen remodeling in the disseminated breast cancer cells. We detect key aspects of this mechanism in lung metastases from patients with breast cancer. In summary, we discover that pulmonary aspartate increases with breast cancer and induces a signaling cascade promoting the growth of lung metastases. Overall design: RNA-seq of matched polysomal/sub-polysomal mRNA fractions extracted from control (shSCR), GRIN2D-knockdown (shGRIN2D), and DHPS-knockdown (shDHPS) 4T1 spheroids cultured in lung-like medium (LLM) supplemented with 700 µM aspartate (ASP) and, in the case of control spheroids, also in the absence of aspartate supplementation (NoASPshSCR).