Cancer cells require a tremendous amount of energy and biomass to grow and spread. To meet these requirements, they hyperactivate their metabolism. This has two major consequences: the generation of elevated levels of oxidative stress and outgrowing the blood supply. As a result, cancer cells often reside in highly oxidative and oxygen-poor environments. Remarkably, cancer cells, unlike healthy cells, can grow and thrive under these extreme conditions. However, the precise pathways through which tumors adapt to these stresses and whether these stresses can be exploited therapeutically remain unknown.
Our laboratory aims to understand the role of metabolic adaptive mechanisms in cancer progression. We use functional genetic screens to identify uncharacterized metabolic pathways that counteract metabolic stress. Our goal is to dissect the molecular underpinnings of these pathways and target them in cancer models as potential therapies.
Antioxidant Pathways in Cancer Progression
Metabolic Adaptations to Hypoxia
Metabolic Liabilities of Therapy-Resistant Tumors
Antioxidant Pathways in Cancer Progression
Tumors experience oxidative stress during all stages of cancer progression due to the generation of reactive oxygen species (ROS) – molecules that react with cellular macromolecules and compromise their function. One major deleterious effect of ROS accumulation is lipid peroxidation, which damages cellular membranes. Excessive accumulation of lipid peroxides disrupts membrane function and leads to a non-apoptotic and iron-dependent form of cell death – ferroptosis. Sensitizing tumors to lipid peroxidation has emerged as a major opportunity for new cancer therapies. Growing evidence suggests lipid peroxides accumulate during radiation therapy, and that mechanisms to suppress ferroptosis result in radioresistance and metastasis.
Execution of ferroptosis requires three factors: ROS, which initiate lipid damage; membrane-incorporated polyunsaturated fatty acids, which are prone to oxidation due to their abundant double bonds; and iron, a transition metal that catalyzes lipid peroxidation. On the other hand, glutathione peroxidase 4 (GPX4) converts lipid peroxides into non-toxic metabolites – thereby allowing cells to resist ferroptosis. Increasing evidence suggests that, in addition to this pathway, tumors rely on alternative mechanisms to counteract lipid peroxidation (Garcia-Bermudez et al. Nature, 2019; Soula et al. Nat Chem Bio, 2020). We hypothesize that cancer cells contain other, uncharacterized mechanisms to suppress lipid peroxidation. Our laboratory aims to identify metabolic genes that promote ferroptosis resistance and test whether disrupting them impairs tumor progression.
Metabolic Adaptations to Hypoxia
Solid tumors frequently outgrow their blood supply and reside in nutrient- and oxygen-poor environments. As oxygen is essential for at least 145 metabolic reactions, a decrease in oxygen levels (hypoxia) impacts the efficiency of metabolic pathways such as mitochondrial oxidative phosphorylation, lipid unsaturation or cholesterol biosynthesis. Furthermore, during hypoxia cancer cells are exposed to oxidative stress – as there is a higher probability for oxygen molecules to generate ROS due to their partial reduction. While it is clear that cancer cells rewire their metabolism to sustain proliferation under oxygen deprivation, the pathways enabling cell growth and survival are not completely understood.
We have previously identified that low oxygen triggers a dramatic decrease in the levels of aspartate, an essential precursor of nucleotide and protein synthesis that becomes limiting for hypoxic cancer cells (Garcia-Bermudez et al. Nat Cell Bio, 2018). By using functional genomics and metabolomic analyses, our lab will systematically identify other limitations of hypoxic tumors and develop therapeutic strategies against them.
Resistance to chemotherapy is widespread and usually involves the existence of a small fraction of cancer cells that survive therapy. A number of mechanisms have been proposed to explain the underlying drug-resistant states such as the rewiring of oncogenic signaling pathways or a pre-defined epigenetic state. However, whether metabolic heterogeneity plays a critical role in this process remains poorly studied. Recently, an example of metabolic dependency has been described: drug-resistant cells strongly depend on the anti-ferroptotic protein GPX4 (Hangauer et al. Nature 2017). This raises the possibility that drug resistant cancer cells possess other unique metabolic features that we could exploit for therapy.
Using a panel of different drug-resistant models, we will define the metabolic pathways that therapy-resistant cells become dependent upon. We aim to uncover metabolic liabilities of refractory tumors and target them using in vitro and mouse models to impair cancer recurrence.
About Dr. Garcia-Bermudez
Javier Garcia-Bermudez received his bachelor’s degree in biochemistry from the Autonomous University of Madrid in Spain. He then went on to obtain his Ph.D. in biochemistry and molecular biology from the same university, studying the role of mitochondrial respiration in cancer progression and stem cell differentiation. In 2016, Dr. Garcia-Bermudez joined Dr. Kivanc Birsoy’s laboratory at The Rockefeller University as an European Molecular Biology Organization Long-Term Fellow and a Leukemia and Lymphoma Society Special Fellow. His postdoctoral work uncovered critical metabolic dependencies of cancers exposed to low oxygen and lipid peroxidation stress.
Dr. Garcia-Bermudez joined the faculty of Children’s Medical Center Research Institute at UT Southwestern in December 2021. He is a Cancer Prevention and Research Institute of Texas scholar and has received a transition award from the National Cancer Institute (NCI-NIH) to support his studies on metabolic liabilities of tumors.
Soula M., Weber R., Zilka O., Alwaseem H., La K., Yen F., Molina H., Pratt D.*, Garcia-Bermudez J.* and Birsoy K.* (2020). Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nature Chemical Biology 16. 1351-1360. *co-corresponding author. (PubMed)
Garcia-Bermudez J., Baudrier L., Bayraktar E., Shen Y., La K., Guarecuco R., Yucel B., Fiore S., Tavora B., Freikman E., Lewis C., Min W., Inghirami G., La K., Sabatini D.M. and Birsoy K. (2019) Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567, 118-122. (PubMed)
Garcia-Bermudez J., La K., Baudrier L., Zhu X.G., Sviderskiy V.O., Papagiannakopoulos T., Snuderl M., Lewis C., Possemato R. and Birsoy K. (2018) Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumors. Nature Cell Biology 20, 775-781. (PubMed)
Garcia-Bermudez J.*, Prasad S.*, Baudrier L., Badgley M.A., Liu Y., La K., Soula M., Williams R.T., Yamaguchi N., Hwang R.F., Taylor L.J., De Stanchina E., Rostandy B., Alwaseem H., Molina H., Bar-Sagi D. and Birsoy K. (2021) Adaptive stimulation of macropinocytosis overcomes aspartate limitation in cancer cells under hypoxia. bioRxiv. (Link)
García-Bermúdez J., Sánchez-Aragó M., Soldevilla B., Del Arco A., Nuevo-Tapioles C. and Cuezva J.M.. (2015) PKA phosphorylates the ATPase Inhibitory Factor 1 and inactivates its capacity to bind and inhibit the mitochondrial H+-ATP synthase. Cell Reports 12, 2143-55. (PubMed)VIEW ALL