According to a new study published in the journal Cell Metabolism, it might be possible to attack cancer by exploiting its own cellular metabolism rather than by employing drugs to kill cancerous cells directly [1].

Study summary Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1a axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROSinduced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.

An insidious enemy

Cancer is a tough nut to crack, despite many advances and breakthroughs in research. Targeted therapies often end up causing the cancer to evolve resistance, weeding out cancer cells that are sensitive to the treatment and leaving around mutated cells that are immune to it; without competitors around, they become free to take over. This evolution makes finding a definitive cancer cure exceedingly difficult, and none is as of yet in sight. Additionally, it is not uncommon for cancer to be blasted out of existence from a given body area, for example through chemotherapy or radiotherapy, only to pop right back somewhere else later on; if any of its stem cells survived, the risk of relapse is not out of the question.

Cancer stem cells (CSCs) are capable of transitioning between a quiescent state and a proliferative state; as you would expect, it is in the latter state that cancer grows. Shifting between quiescent and proliferative states helps cancer to evade treatment and spread in the body.

Exploiting metabolism







However, these two states rely on different energy sources. Our cells depend on two metabolic pathways for their energy needs: glycolysis, which involves the breakdown of glucose, and oxidative phosphorylation, which takes place in the mitochondria of the cells. The first pathway is independent of oxygen, whereas the second, as the name suggests, heavily relies on it. When cancer cells are quiescent, they run on glucose; when they are in the proliferative state, their energy comes from mitochondria.

Rather than throwing drugs at it, the authors of the study tried to attack cancer by pulling the plug on both energy sources. In mice affected by breast cancer, the researchers intervened pharmacologically on mitochondria to cut the energy supply of proliferative CSCs, and they also interfered with the glycolysis pathway. As a result, cancer stem cells in both states were eliminated, immediately suppressing tumor growth, the cancer’s ability to initiate new tumors, and metastasis, which is the spreading of the cancer from its original site to secondary sites in the body.

Conclusion

As always, it’s early to tell whether this approach may translate to humans. One limitation of this study, pointed out by the researchers themselves, is that the mice were immunodeficient; as the immune system also fights cancer, using animals with normal immune systems might have skewed the results. It remains to be seen what effects the same treatment will have in immunocompetent animals, and, of course, whether the method will be applicable to people. The scientists are hopeful that clinical translation might be possible in the near future.

Literature







[1] Luo, M., Shang, L., Brooks, M.D., Luker, G. D., Spitz, D. R., Wicha, M. S. (2018). Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. Cell Metabolism, 28, 69-86.