Ricerc@Sapienza

Metabolic reprogramming is needed for the growth and proliferation of cancer cells. One carbon metabolism (1C-metabolism), a complex network of reactions involving folate compounds, supports proliferation by providing nucleotides, NADPH and methylation potential. Aberrant activation of 1C-metabolism is thus an essential process in cancer pathogenesis.
In 1C-metabolism, the enzyme serine hydroxymethyltransferase (SHMT), expressed both in the cytoplasm (SHMT1) and in mitochondria (SHMT2), acts as a metabolic checkpoint, channelling one-carbon units to nucleotide synthesis and/or production of antioxidants, depending on the metabolic demand of different types of cancers.
Our working hypothesis is that selective targeting of SHMT offers clues to control cell proliferation by acting on these processes and by affecting the epigenetic regulation of DNA and RNA.

This project, based on our unique expertise and previous results in the field of SHMT biochemistry, biology and inhibition, is focused on two related but partially independent aims:
AIM1) determine the SHMT-dependent profile of metabolic vulnerabilities in human cancers which show different expression levels of the two SHMT isoforms (SHMT1/SHMT2).
AIM2 2) find strategies to interfere with 1C-metabolism in cancer by targeting SHMT.

We aim to produce new data on the critical importance of SHMT in the development and/or maintenance of cancer, including:
- Characterization of cytosolic, mitochondrial and nuclear SHMT activity and dynamics in cancer cells, also under hypoxic
conditions.
- Elucidation of the interplay among different SHMT isoforms and with metabolites.
- Analysis of dTMP synthesis and methylation events controlled by SHMT.
- Identification of SHMT direct/indirect inhibitors and study of their impact on cell proliferation and cell death in different
tumors.

Intervention on serine metabolism targeting SHMT may open new translational opportunities for drug development and biomarker identification.