Cancer cells need to readjust their metabolism to obtain the energy and metabolites required to fulfill both energetic and anabolic demands and sustain a high rate of cell growth and division. Despite providing a potential Achilles heel that could be exploited for therapeutic purposes, surprisingly little is known about the molecular mechanisms regulating such a metabolic switch.

In this regard, we found that the NAD- dependent histone deacetylase SIRT6 is a master regulator of glycolysis and a critical tumor suppressor gene. SIRT6 is a member of the conserved Sirtuin family of protein deacylases that integrate metabolic networks with cellular growth responses, and have been implicated in the control of aging, regenerative processes, and cancer.

Our results demonstrate that loss of SIRT6 promotes a robust metabolic reprogramming that is sufficient to drive tumorigenesis bypassing major oncogenic signaling pathway activation, suggesting a role for SIRT6 in tumor initiation. In genetically engineered mouse models, SIRT6 inactivation drives the development of highly invasive intestinal cancer, which exhibits a pronounced switch towards glycolysis. Importantly, 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.

These results suggest that rewiring of metabolic pathways may be established extremely early during the process of transformation. Indeed, our recent data indicates that glucose metabolism is a crucial regulator of stem cell activity and tumor initiating potential in the intestine.

Metabolic regulation of stem cell fate during tissue homeostasis and tumorigenesis

Both embryonic and adult stem cells exhibit very specific metabolic properties that are distinct from their differentiated progeny. Importantly, this metabolic reprogramming is not a bystander adaptation but it is an active regulator of stem cell fate that dynamically drives proliferation, lineage commitment and differentiation. Remarkably, many features of stem cell metabolism are strikingly similar to the ones observed in cancer cells. As most epithelial cancers originate from transformation of tissue stem cells, it is then reasonable to speculate that rewiring of specific metabolic pathways could be an early event during tumorigenesis and, thus, be involved in tumor initiation. Following up this idea, our laboratory is interested in elucidating the role of metabolism on stem cell dynamics and its contribution to tumor initiation and growth, and how the crosstalk between metabolism and epigenetics regulates stem cell fate in health and disease.

Metabolic heterogeneity and evolution of cancer

Despite the many efforts made to elucidate the metabolic adaptations of cancer cells, there is a complete lack of understanding of the specific steps during the tumorigenic process when this metabolic rewiring occurs, its dynamic regulation during tumor progression and its biological consequences. Furthermore, our recent data suggests that tumors are metabolically heterogeneous, with different subsets of cancer cells exhibiting specific metabolic properties. However, the nature of this metabolic heterogeneity, its role on tumor progression and its regulatory mechanisms remain largely unexplored. In this regard, our laboratory aims to define the compartmentalization and spatial-temporal evolution of metabolic reprogramming during tumorigenesis in vivo. To do so, we have developed novel systems that enable us to monitor metabolism in vivo at single cell level and further characterize stepwise metabolic alterations within the physiological context of tumors. These studies will contribute to a broader understanding on how cancer metabolism regulates tumor initiation and progression and will potentially provide the rationale to target metabolism to improve current therapies and reduce cancer mortality.

Metabolic crosstalks in the tumor microenvironment

Tumors are not only formed by a heterogeneous population of cancer cells, but also by stromal cells and immune cells, and the interaction among them will dictate whether the tumor progresses. In this context, recent data indicates that stromal and immune cells rely on specific metabolic pathways for their function. However, little is known about the precise role of the metabolic crosstalk between cancer cells and stromal/immune cells on tumor progression. Using our novel reporter systems to track metabolism in vivo at single cell resolution, our laboratory is interested in analyzing the energetic requirements of every cell type within the tumor mass and whether metabolic cooperation/competition between them influences tumor initiation, growth and progression. Special attention is given to the characterization of the functional role of metabolism in shaping immune responses against tumors and the identification of novel metabolic interventions favoring anti-tumoral immune responses.