Metabolic Pathways and Liabilities in Cancer Cells
Cancer cells use reprogrammed metabolic pathways to grow and resist stress encountered in the tumor microenvironment. These reprogrammed pathways facilitate malignant transformation and enable tumor progression. Identifying such pathways will allow us to better understand the biology of cancer and uncover new therapeutic targets. We use metabolomics, metabolic flux analysis, cell biology and animal models of cancer to study how tumor cells generate energy, build macromolecules and maintain redox balance. We seek to identify the processes, both intrinsic and extrinsic to the cancer cell, that affect tumor metabolism and to discover context-specific metabolic vulnerabilities that might provide a basis for new treatments.
As an example of our approach, we identified a new mechanism by which the MYC oncoprotein coordinates cell growth in small cell lung cancer (see figure – Huang et al., J Clin Invest 202). MYC transcriptionally activates many pathways, including well-known pathways of nucleotide and ribosome biogenesis, that need to be synchronized to culminate in cell proliferation. We discovered that MYC’s ability to activate guanosine triphosphate (GTP) synthesis is required to activate the ribosome program. These two processes are mechanistically linked by the small GTP-binding proteins GPN1 and GPN3, both of which are MYC targets and whose GTPase activity helps guide RNA Polymerase I to the rDNA to initiate ribosome biogenesis. Our findings provide an example of how MYC coordinates multiple biosynthetic programs in parallel to induce cell growth. Of note, reliance on this mechanism is prominent in chemotherapy-resistant small cell lung cancers, which are among the most treatment-refractory tumors but tend to display MYC activation. We report that these tumors can be treated in mice with clinically-available inhibitors of GTP synthesis.
