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.
This project will develop a multidisciplinary research platform for the understanding of how metabolic reprogramming in cancer is controlled by SHMT.
Metabolism in general and specifically folate metabolism have benefitted tremendously from the last years technical and conceptual revolution in the field of cancer development. Entirely new insights have continued to emerge as our understanding has grown, providing exciting new possibilities for both fundamental processes and clinical applications. Results will provide advanced stratification rational for patients prognosis.
As briefly summarized in the previous sections, compelling evidence shows the absolute dependence of growing cells on intrinsic 1C-metabolism and the potential for its rational therapeutic targeting, exploiting its metabolic vulnerabilities. The 1C-metabolism offers several possibilities for tailor-made intervention because the enzymes belonging to this pathway are differentially expressed in different cells, thus leading to diverse metabolic vulnerabilities. The nutrient dependence of serine metabolism in different types of cancer may also unmask connections with other metabolic pathologies, such as type 2 diabetes.
Our project aims to leverage this knowledge by studying if and how modulating 1C-metabolism and its cross-talk with energy metabolism can target a highly refractory form of cancer, ie lung cancer. Here we aim to advance our basic knowledge (see as an example the goal of elucidating the structure of the dTMP synthesis nuclear complex) but also to search for a wider translational benefit, in the form of a new generation of effective inhibitors and modulators targeting 1C-metabolism. The newly built HypACB facility will be strategic to strengthen our knowledge on energy metabolism and hypoxic studies.
Determination of the structure of nuclear complex formed by SHMT1, Thymidylate Synthase (TS) and Dihydrofolate reductase (DHFR) by X-ray crystallography is undoubtly a high-risk goal but, if successful, will give an invaluable contribution to cancer biology, also considering the wealth of currently used drugs targeting nuclear thymidylate synthesis. This is a challenging goal and we might not obtain crystal suitable for X-ray analysis. In this case we will explore the possibility to determine the supercomplex structure by Cryo-Electron Microscopy, which has proved to be a powerful technique to solve large complexes. This technique is being implemented in our Department and will provide and implement novel, up-to-date tools for protein structural biology in Sapienza University.
Our team also plans to develop novel methodologies to send small molecules in the mitochondria, a highly challenging goal which, if successful, may have deep impact on several pathological states involving mitochondrial defects.
Altered metabolic states in health and disease offer tremendous opportunities to develop novel therapeutic strategies, but might also provide novel methods in diagnostic imaging. This is very relevant for lung cancer, which shows one of the poorest survival outcomes of all cancers, with over two-thirds of patients diagnosed at an advanced stage, when curative treatment is no longer feasible. Early diagnosis of lung cancer is thus a major goal to improve survival. As suggested by Hensley and DeBerardinis, we should consider the metabolism of cancer cells as completely different from that of a healthy cell (Hensley, C.T., et al., J Clin Invest, 2015. 125(2): p. 495-7). The identification of novel biomarkers based on metabolic changes in lung cancer could provide clear information right from the early stages of the disease and enable one to follow its pathophysiologic dynamics.
Lastly, our project fully meets the requirements and suggestions put forward by the Horizon 2020 Research and Innovation Programme, to strengthen personalized medicine, in order to gain insight in both etiologies and underlying mechanisms that modulate progress of many diseases across the full course of the disease.