MAY 31, 2018, NEW YORK — A Ludwig Cancer Research study has uncovered an entirely novel mechanism by which cells enter a state of dormancy as tissues starved of oxygen become increasingly acidic. The study, led by Chi Van Dang, scientific director of the Ludwig Institute for Cancer Research, has potentially significant implications for cancer therapy: Large swaths of solid tumors are often deprived of oxygen, and cells in such patches are thought to be a major source of drug resistance and disease relapses.
Published today in the journal Cell, the study details how in response to acidity cells turn off a critical molecular switch known as mTORC1 that, in ordinary conditions, gauges the availability of nutrients before giving cells the green light to grow and divide. That event, Dang and his colleagues show, shuts down the cell's production of proteins, disrupting their metabolic activity and circadian clocks, and pushing them into a quiescent state. They also demonstrate that this acid-mediated effect might be relatively easy to reverse–a finding that could help improve a variety of cancer therapies.
"In tumors grafted into mice, we see mTOR activity in spotty places where there's oxygen," says Dang who is also a professor in the Molecular and Cellular Oncogenesis Program at The Wistar Institute. "But if you add baking soda to the drinking water given to those mice, the entire tumor lights up with mTOR activity. The prediction would be that by reawakening these cells, you could make the tumor far more sensitive to therapy."
Baking soda had previously been reported to enhance cancer immunotherapy by one of the co-authors of the new study, Robert Gillies of the H. Lee Moffitt Cancer Center, though the mechanism underlying the effect was unclear.
Dang's team, including co-corresponding author Zandra Walton, an MD-PhD student at the University of Pennsylvania Perelman School of Medicine, discovered that mechanism through an intricate series of experiments done at the University of Pennsylvania and Dang's Ludwig lab at the Wistar Institute. It centers on the behavior of lysosomes–a sack-like cellular organelle that digests proteins and that mTOR moves to when it is ready for action.
The researchers show that in acidic conditions protein motors propel lysosomes carrying mTOR away from the area around the nucleus, where they're ordinarily located. This separates mTOR from a protein required for its activation, RHEB, which continues to hang around at that location. Lacking one of its key activation signals, mTOR remains dormant, suspending the synthesis of proteins–including the components of the cell's molecular clock–along with most metabolic activity.
"Cells don't want to make proteins or other biomolecules when they're under stress," says Dang. "They want to slow things down and only awaken when things return to normal."
The researchers show that baking soda can reverse this effect. When given to mice in their drinking water, it surprisingly sufficed to neutralize the acidity of hypoxic patches in tumors. This sent lysosomes zipping back to the nuclear periphery in cells–where RHEB was waiting–and restored the activity of mTOR.
All this is relevant to cancer because researchers have long known that quiescent cells cannot typically be killed by chemotherapy. Notably, Dang and his team also found that T cell activation, which is essential to most immunotherapies, is similarly compromised under acidic conditions.
"We started out with a question about oxygen starvation and the circadian clock, and we ended up discovering a new mechanism by which acidic conditions in tissues shut off a lot of things–including the cell's molecular clock," muses Dang.
The finding that something as simple as baking soda could possibly help reverse this effect and render quiescent cancer cells susceptible to cancer therapies excites Dang.
"The concept is so easy," he says. "It's not some $100,000 per year drug. It's literally just baking soda." Dang and his team are now looking into how acidity might affect immunotherapy and further exploring the acid-induced quiescence of cancer cells.
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The study was supported by Ludwig Cancer Research, the US National Institutes of Health, the Department of Veterans Affairs, the Patel Scholar Award, the Bloomberg-Kimmel Institute of Cancer Immunotherapy and the US National Cancer Institute.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.
For further information please contact Rachel Reinhardt, [email protected] or +1-212-450-1582.
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Rachel Reinhardt
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http://dx.doi.org/10.1016/j.cell.2018.05.009
