Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis

Abstract

Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs target mainly the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that enable cell plasticity and foster treatment resistance and tumor escape. Using a panel of anti-cancer drugs, we uncovered that antifolates, despite their strong growth arrest function, do not at all reduce the cancer cell's motility potential, indicating that nucleotide synthesis is dispensable for cell motility. Prolonged treatment even selected for more motile cancer subpopulations. We found that cytosolic inhibition of DHFR by MTX only abrogates cytosolic folate cycle, while mitochondrial one-carbon cycle is still highly active. Despite a decreased cellular demand for biomass production, de novo serine synthesis and formate overflow are increased, which suggests that mitochondria provide a protective environment that allows serine catabolism to support cellular motility during nucleotide synthesis inhibition. Enhanced motility of growth-arrested cells was reduced by inhibition of PHGDH-dependent serine de novo synthesis and genetic silencing of mitochondrial one-carbon cycle. In vivo targeting of mitochondrial one-carbon cycle and formate overflow strongly and significantly reduced lung metastasis formation in an orthotopic breast cancer model. In summary, we identified mitochondrial serine catabolism as a targetable, growth-independent metabolic vulnerability to limit metastatic progression.

Metabolic plasticity of serine metabolism is crucial for cGAS/STING-signalling and innate immune response to viral infections in the gut

“…As S/G starvation led to a compensatory activation of the SSP, which might directly feed into GSH synthesis we combined S/G starvation with the inhibition of PHGDH, the rate limiting enzyme of the SSP pathway, by using the specific and competitive inhibitor BI-4916 (BI, Fig. 3A) (43,44). As expected, BI treatment blocked SSP and dual perturbation with BI and S/G starvation further reduced intracellular serine and GSH levels, confirming the efficacy of our treatment (Fig.…”