In a series of research papers from 2013 to 2021, Weill Cornell Medicine researchers showed that in a phase II clinical trial when patients who had high-risk triple-negative breast cancer (TNBC) were treated with a drug that lowers the levels of copper in their bodies, it prolonged the period of time before their cancer recurred and spread or metastasized. In the current study, published Dec. 15 in Nature Communications, and led by first author Divya Ramchandani, a research associate in Cardiothoracic Surgery at Weill Cornell Medicine, the investigators used animal models to take a closer look at why that was the case.

“One of the defining features of TNBC is that it’s highly aggressive, difficult-to treat form of disease, with high rate of metastatic recurrence and few treatment options,” said co-senior author Dr. Vivek Mittal, director of research at the Neuberger Berman Lung Cancer Center and the Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine. “Even after surgery and other treatment, the rates of recurrence are high, which tends to happen early on. As a result, better treatments that focus specifically on this type of cancer are needed.”

Many of the biological processes that take place inside cells require metal atoms. Although iron is perhaps more well-known, copper has begun to emerge to be an important player. Copper is required for a process called oxidative phosphorylation (OXPHOS), which cells use to generate energy in organelles called mitochondria. Dr. Mittal showed that metastatic cancer cells in TNBC had high levels of intracellular copper and elevated levels of OXPHOS compared to non-metastatic cells. The researchers hypothesized that metastatic cells may require a lot of energy to spread to other parts of the body and set up shop, blocking the availability of copper, thereby cutting off their power source, might be a good way to prevent these cells from traveling.

To lower levels of copper, the researchers in both the earlier clinical trial and the recent animal research used a drug called tetrathiomolybdate (TM), which is being developed to treat a copper-storage disorder called Wilson’s disease. In mouse models of TNBC, they found that when they depleted the levels of copper in the body, the primary tumors continued growing while the cancer’s ability to metastasize was greatly reduced.

A closer look at the cancer cells treated with TM found that these cells changed their metabolism in a way that made it harder for them to generate energy. Interestingly, this failing energy status triggered a crucial energy sensor AMP-activated protein kinase (AMPK). In a separate study, the researchers also found that lowering copper levels affected collagen remodeling in the so-called premetastatic niche — areas of the body where it’s easier for rogue cancer cells to establish themselves. This helped explain how TM may make it more difficult for traveling TNBC cells to colonize distant organs.

“This paper is based on research that started in the clinic, which we brought back to the lab,” said co-senior author Dr. Linda Vahdat, who is professor of medicine at Weill Cornell Medicine, a medical oncologist at MSK and chief of medical oncology and clinical director of cancer services at Norwalk Hospital. “Now it has morphed into some very interesting science that we can move forward into a bigger clinical trial.”

“We can use this information to plan our large, randomized trial in breast cancer,” Dr. Mittal said. The trial, which will be a phase II trial enrolling 177 patients, will look at the use of TM as an adjuvant treatment (one given after other treatment is completed) to reduce the risk of the cancer coming back in patients with TNBC. The study is expected to begin recruiting patients in the fall of 2022 through the Translational Breast Cancer Research Consortium, supported by the Breast Cancer Research Foundation, with additional support from the NCI NExT program.

In the earlier trial, Dr. Vahdat said, the patients had very few side effects from the TM, which is taken two to three times a day as a pill. “We deplete the copper in patients to the level where normal cell functions can still take place, but tumor-related processes cannot,” she said.

Lab research will be an important component of the upcoming trial as the goal is to figure out the right treatment for the right patient at the right time. Investigators will study tissues from the patients to analyze the metabolic aspects of both tumor and healthy tissues. Drs. Mittal and Vahdat plan to expand upon these findings using a recently awarded $2.8 million grant from the National Cancer Institute to study copper-mediated metabolic reprogramming and extracellular matrix alterations in TNBC metastasis.

The researchers found that the seasonal availability of carbon produced by phytoplankton is shifting poleward and appears for longer than in previous decades. The discovery will enhance scientists’ understanding of carbon cycling and nutrient availability in this rapidly warming and changing environment.

During photosynthesis, all plants convert carbon dioxide into food by harnessing energy from the sun. The food they create, in the form of organic carbon, is critical to life. This process is called primary production and plays a major role in the global carbon cycle. In the ocean, almost all primary production is performed by phytoplankton.

“Everything depends on the carbon produced by phytoplankton, no matter where you are in ocean waters,” said Bigelow Laboratory Senior Research Scientist Paty Matrai, one of the paper’s co-authors. “If there is no primary production, then there is no new carbon being created, and the many animals that depend on it have nothing to feed on.”

Arctic phytoplankton growth patterns have already been significantly altered due to climate change. The fish that feed on them have had to adapt, along with the industries that rely on them. A better understanding of these changes is needed to plan ahead.

The researchers looked at a 10-year time period from 2008 to 2017 in seven regions around Greenland to understand where and when primary production was happening. They found the rates to be higher in southern regions where water is more influenced by the North Atlantic. They also discovered that phytoplankton blooms began in the south around April and in the north around June.

“There is extreme seasonality and great diversity in what’s happening with respect to primary production in these waters,” Matrai said. “Greenland sits at an influential location, and understanding the waters around it may give us unique insights into global ocean processes.”

Greenland is at the intersection of complex interactions between Arctic Ocean and Atlantic Ocean currents, and the waters off its shores are part of both systems. As the planet warms, more temperate conditions, along with the nutrients and organisms that prefer them, are moving up from the south.

Its waters are also a mixing spot for saltwater and melting freshwater. Over 80 percent of its landmass is covered by the Greenland ice sheet. As it melts due to global warming, it sends an influx of cold freshwater into the ocean from the north. This could have significant impacts on the physical and biological processes in the North Atlantic including ocean convection, nutrient availability, and primary production.

The waters around Greenland are notoriously difficult to study. Rough weather, complex ocean conditions, and shifting sea ice make sampling dangerous. Although the fjords on its western side have been better studied, less is known about the fjords and continental shelf to the east.

The researchers used two independent mathematical models to calculate primary production around the island. One was based on ocean color, which can be used as a proxy for phytoplankton and other life, and the other on ocean biology and physical characteristics.

The team also found that most of the carbon from primary production around Greenland sinks, which impacts ocean ecosystems below surface waters. In contrast, scientists have long thought unused carbon that remains at the surface becomes carbon dioxide and returns to the atmosphere.

The study showed that up to 75 percent of the annual production is exported deep into the ocean, with the highest amounts sinking in the regions closer to the Arctic. This means the carbon could play an additional, unexpected role in global cycles because it would be swept into deep ocean currents moving around the planet.

Most organisms live in surface waters of the ocean, where sunlight fuels photosynthesis. Scientists have used this region as the model for how food webs and nutrient cycles operate. However, when carbon produced near the surface sinks, it becomes accessible to a different set of organisms. This opens up new possibilities for ecosystem dynamics and discovery.

The researchers aim to build on these results to understand longer-term patterns of primary production, how they will be affected by climate change, and how that will affect marine life.

“As melting sea ice allows sunlight to reach more ocean waters, it creates additional habitats for photosynthetic organisms and more potential for primary production,” Matrai said. “Better understanding the role of primary production can help us anticipate changes in this critical environment and provide an opportunity to adapt to them.”

The research was published in the journal Progress in Oceanography by lead author Maria Vernet from the Scripps Institution of Oceanography at the University of California, San Diego.

“Sesame is the ninth most common childhood food allergy in the US, yet many people don’t recognize it on food labels, or it’s missing entirely” says allergist Katie Kennedy, MD, ACAAI member and senior author on the paper. “What we discovered in our study was that amongst those who reported events related to accidental ingestion of sesame, many reported they didn’t know that words such as ‘tahini’ meant sesame. Because the word ‘sesame’ is often not used on labels, accidents happen at a greater rate.”

The study examined 379 self-reported events related to sesame involving 327 individuals with 360 distinct adverse clinical reactions. 19 events involved a sesame labeling issue that did not result in a clinical reaction. Most of the reports (85%) were from parents providing information on events with their children.

“About 48% of the allergic reactions required hospitalizations or an emergency room visit,” says allergist Kim Nguyen, MD, ACAAI member and co-author of the paper. “Most of the events (63%) occurred at home; about 11% of events occurred at a restaurant, 5% at a friend’s house and 4% of events occurred at school. The most common reason for reporting an event was the occurrence of an allergic reaction following ingestion (99%) as opposed to contact-only exposure.”

“Some of the reports were due to products declared as containing ‘spices’ or ‘natural flavors’ and required consumers to call the company or manufacturer to clarify the ingredients,” says Dr. Kennedy. One of the reported events occurred in a child with a known sesame allergy, and she had eaten meatloaf made with breadcrumbs. The parents later learned that the “spices” labeled on the breadcrumbs contained sesame.

The authors conclude that clear and specific product labeling for sesame is crucial for the prevention of adverse reactions, especially anaphylaxis, in food-allergic people.

Story Source:

Materials provided by American College of Allergy, Asthma, and Immunology. Note: Content may be edited for style and length.