Research Topic: Mass spectrometry approaches for studying cancermetabolism
Mass spectrometry based metabolomics is a widely usedapproach in biomedical research. However, current methods coupling massspectrometry with chromatography (LC-MS) are time-consuming and not suitablefor high-throughput analysis of thousands of samples. In a paper recentlypublished in Nature Communications wedescribe an approach for high-throughput metabolomics based on flow-injectionmass spectrometry (FI-MS) in which samples are directly injected to theionization source. We show how MS overloading with this approach can be overcomeby analyzing the distribution of ion m/z values and computationally determininga series of optimal scan ranges for getting highly reproducible data. In afollow up work, we developed a sub one-minute LC-MS based metabolomics methodand demonstrate comparable analytical performance to a standard 25 minutesLC-MS method. We are currently using these approaches as a basis for developingearly diagnosis methods for the top-5 frequent cancers in Israel basedthousands of serum samples obtained from Rambam Hospital.
Another focus of my research was developing a LC-MS basedmethod for investigation of one-carbon (1C) metabolism. Folate metabolism supplies 1C units for biosynthesisand methylation and has long been a target for cancer chemotherapy. In arecently published article in CellMetabolism we showed that while mitochondrial metabolism is considered themajor source of 1C units in cancer, it is actually the cytosolic pathway that predominantlyproduce 1C units in a variety of tumors under physiological conditions.Tumor-specific reliance on cytosolic 1C flux is associated with poor capacityto retain intracellular folates, which is determined by the expression of Reducedfolate carrier (RFC1). We showed that silencing SHMT1 (cytosolic 1C producingenzyme) in cells with low RFC1 expression impairs pyrimidine biosynthesis andtumor growth in vivo. Overall, ourfindings reveal major diversity in cancer cell utilization of the cytosolicversus mitochondrial folate cycle across tumors and RFC1 expression as a markerfor increased reliance on SHMT1.
