Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

Comparison of predictive blood transfusion scoring systems in trauma patients and application to pre-hospital medicine.

Hemorrhage leads to 30% to 40% of trauma deaths, with up to 50% of these deaths transpiring before hospital arrival. There is a growing amount of experience and research with prehospital blood administration, but few tools exist to identify the need and impact of a prehospital blood program in a community. Validating a blood use prediction tool locally will allow us to apply that validation to prehospital patients in other communities. Multiple algorithmic scoring tools that predicted the use of blood products were assessed using data from Baylor Scott and White Memorial Hospital, a level I trauma center. A total of 100 men and 51 women were included in the study, 99 of whom received a blood transfusion within 2 hours of hospital arrival. Comparing the scoring systems using our internal data, we found that three scoring systems were approximately equal at determining the need for blood products: Criteria A for the Zhu et al scoring system had a specificity and positive predictive value (PPV) of 92% while maintaining a sensitivity and negative predictive value (NPV) of 48%. Similarly, the EBTNS scoring system with a cutoff of ≥6 resulted in a specificity of 90%, PPV of 91%, sensitivity of 56%, and NPV of 52%. Lastly, the ABC scoring system with a cutoff of ≥2 had a specificity of 94%, PPV of 91%, sensitivity of 38%, and NPV of 56%. These scoring tools can be used in the prehospital setting to predict the need for blood in geographic areas in order to help with asset utilization.

The gut microbial metabolite formate exacerbates colorectal cancer progression.

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.