Carlos Sebastian, Ph.D.
Metabolic reprogramming and its role in tumor initiation and progression
Most cancer cells need to readjust their metabolism to obtain the energy and metabolites required to fulfill both the energetic and anabolic demands of a rapidly growing tumor. The best-known example of this metabolic reprogramming is the enhanced glucose uptake and metabolism exhibited by cancer cells. While normal cells catabolize glucose to pyruvate through glycolysis, which will enter the mitochondria to be fully oxidized in the Krebs cycle, cancer cells shift glucose metabolism towards “aerobic glycolysis”, where glucose-derived pyruvate is converted to lactate instead (the so-called “Warburg effect”). Besides glucose metabolism, it has recently become clear that most of the core metabolic pathways of a cell are rewired during tumorigenesis, allowing cancer cells to meet three basic needs to sustain cell growth and proliferation: ATP production, biosynthesis of precursors to build up macromolecules and maintenance of cellular redox status. Despite being previously thought to be a mere consequence of a faster proliferation, recent work has shown that this metabolic reprogramming is a fundamental trait of all cancer cells and it is directly regulated by oncogenes and tumor suppressors. In line with this, specific metabolic adaptations of tumor cells are required for tumorigenesis and, thus, metabolic reprogramming has been upgraded to be a hallmark of cancer. However, whether this metabolic switch can drive tumorigenesis remains as yet poorly understood. Furthermore, despite many efforts made to identify metabolic properties of cancer cells, there is a complete lack of understanding of the specific steps in the tumorigenic process when this metabolic rewiring occurs, its biological consequences, and the precise molecular mechanisms driving this metabolic reprogramming.
Our laboratory has described SIRT6 as a potent tumor suppressor that epigenetically controls cancer metabolism (Sebastian et al., Cell 2012). SIRT6 is a member of the conserved Sirtuin family of histone deacetylases that integrate metabolic networks with cellular growth responses, and have been implicated in the control of aging, genomic stability, cellular responses to stress, metabolism and cancer. Via its H3K9/K56 deacetylase activity, SIRT6 co-represses Hif1α and MYC in cancer cells, directly regulating the expression of key glycolytic and ribosomal protein genes. Importantly, loss of this tumor suppressor promotes a robust metabolic reprogramming that is sufficient to drive tumorigenesis, bypassing major oncogenic signaling pathway activation. Furthermore, inhibition of glycolysis by genetic or chemical means abrogates the tumorigenic potential of SIRT6-deficient cells, highlighting a dominant and driving role of glucose metabolism reprogramming in tumor initiation. Indeed, our preliminary results suggest a role for SIRT6 in regulating the number and activity of tumor-initiating cells by controlling glucose metabolism. Together, these findings represent one of very few direct demonstrations of the centrality of tumor metabolism to the process of cancer initiation and growth.
Conclusions and perspectives:
For years, it was thought that the metabolic reprogramming observed in cancer cells was a consequence of their increased proliferation due to the mutation and activation of signal transduction pathways. However, our previous work has demonstrated that this metabolic reprogramming is sufficient to promote tumorigenesis independent of canonical transforming events. Following up this idea, our laboratory aims to study the metabolic evolution of cancer and its regulatory mechanisms, by focusing on the study of the metabolic requirements of cancer cells during tumor initiation and progression, and the functional interplay between metabolic reprogramming and other genetic and epigenetic programs involved in different stages of the tumorigenic process. These studies will provide a comprehensive picture of the step-wise contribution of metabolic reprogramming to tumorigenesis, which will be used to design new therapeutic approaches targeting metabolic pathways.