Ludwig researchers describe how acidity turns oxygen-starved cancer cells dormant and drug resistant—and a potentially easy way reverse the effect.
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.
Learn more: HOW MIGHT BAKING SODA BOOST CANCER THERAPY?
Receive an email update when we add a new CANCER THERAPY article.
The Latest on: Cancer therapy
via Google News
The Latest on: Cancer therapy
- Genomics Guide Treatment Escalation, De-Escalation in HR+ Breast Cancer on February 21, 2019 at 9:52 am
A greater understanding of the genomics of patients with hormone receptor (HR)–positive breast cancer is enabling physicians to offer more personalized de-escalated and escalated treatment strategies ... […]
- City of Hope Awarded Lymphoma Specialized Programs of Research Excellence (SPORE) Grant from National Cancer Institute on February 21, 2019 at 9:37 am
David M. Colcher, Ph.D., City of Hope professor in molecular imaging and therapy, is also a scientific principal investigator. Fighting STAT3 in non-Hodgkin’s lymphoma Non-Hodgkin’s lymphoma (NHL) is ... […]
- PET Scans Show Biomarkers Could Spare Some Breast Cancer Patients from Chemotherapy on February 21, 2019 at 9:09 am
Newswise — In an effort to further individualize therapy and avoid over-treating patients, researchers at the Johns Hopkins Kimmel Cancer Center report a new study using PET scans has identified a bio... […]
- Myovant- "Value Creation" in Cancer Treatment on February 21, 2019 at 8:03 am
In their most recent quarterly update, the company highlighted Relugolix and emphasized that all important timelines remain on track for top-line Phase III data readouts in uterine fibroids from ... […]
- Drug prices based on success could speed up cancer patients' treatment on February 21, 2019 at 7:05 am
Paying for cancer drugs based on how well they work in practice could help patients get new treatments faster, according to a Cancer Research UK report published today. As well as providing value ... […]
- After the Diagnosis: Treatment Options for Kidney Cancer on February 21, 2019 at 6:48 am
Most often, the cancer is found incidentally. A CT, or computed tomography, scan is done, for instance, because a person has abdominal pain or some other (usually unrelated) symptoms. And when ... […]
- Keytruda May Play a Role in Treatment of Patients with Non-Muscle Invasive Bladder Cancer on February 21, 2019 at 6:28 am
After patients with non–muscle invasive bladder cancer fail to respond to treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, Keytruda (pembrolizumab) may induce responses in these high-risk ... […]
- Cancer drug pricing gets in the way of treatment in developing countries on February 21, 2019 at 6:17 am
Vikash Sewram does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond ... […]
- Alliance for Cancer Gene Therapy honors cancer pioneer Dr. Carl June at April 18 Gala on February 21, 2019 at 6:16 am
Alliance for Cancer Gene Therapy (ACGT), the nation's only nonprofit dedicated exclusively to funding cancer cell and gene therapy research, is celebrating its 18th anniversary with a very special Awa... […]
via Bing News