Metastasis is the leading cause of death in most patients with breast cancer. Strikingly, metastatic cancer cells acquire additional features (not seen in the primary tumor) that aid survival and growth in the new conditions of the distant site. In addition, secreted factors from primary tumors can alter organs creating a more permissive environment for metastasizing cells called pre-metastatic niche. Notably, it remains unknown whether nutrient availability in the metastatic organ, which is a crucial aspect enabling metastasis formation, is altered during pre-metastatic niche formation in order to prepare the niche. To study this, we induced pre-metastatic niche formation in mice by injecting tumor-secreted factors (TSF) and analyzed nutrient concentration in the lung. We found fatty acids to be highly abundant and a TSF-specific increase of the fatty acid palmitate in the lung niche. Furthermore, mass spectrometry imaging showed that lung metastases were enriched in palmitate-containing lipids compared with adjacent non-cancerous tissue, suggesting a key role of palmitate in metastatic lesions. Mechanistically, we discovered that metastatic cells use the available palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1A)-dependent manner. Moreover, we found that only palmitate but no other fatty acids promotes the expression of lysine acetyltransferase 2A (KAT2A). In turn, KAT2A acetylates the transcription factor NF-kB in the presence of palmitate. This favors its nuclear location and activates a pro-metastatic transcriptional program specifically in metastasis. Strikingly, inhibition of CPT1A or KAT2A significantly reduces metastasis formation in mice. Further highlighting the relevance of our findings, we found that CPT1A and KAT2A proteins as well as NF-kB gene signature are highly expressed in metastases from palmitate-rich organs of patients with breast cancer. In conclusion, we identified that palmitate availability is primed in organs of future metastasis inducing a pro-metastatic NF-kB signaling in the arriving cancer cells. However, why palmitate has such a unique pro-metastatic effect compared to other fatty acids with similar biochemical properties remains largely elusive. Our newly established group discovered that palmitoylation, a reversible post-translational protein modification driven solely by palmitate, is essential for metastasizing breast cancer cells. We are now investigating how the dynamics of palmitoylation promote metastasis and whether palmitate-rich conditions (e.g under high-fat diet) can potentiate palmitoylation engaging in pro-metastatic signaling. Our results will help to define potential palmitoylation-based therapies to prevent or treat metastases.

Trabajo presentado en Hinterzartener Kreis der DFG für Krebsforschung Lake Como Cancer Meeting from Molecular Mechanisms to Cancer Therapy, celebrado en Cadenabbia (Italia), del 16 al 19 de mayo de 2024