1. Neff Newitt, Valerie

Article Content

Swarnali Acharyya, PhD, is well aware of the fatal danger of metastatic cancer. It is an area of acute interest she shares with her husband, Anup Biswas, PhD, at the Institute for Cancer Genetics at Columbia University Medical Center. However, there is another primary focus that proves just as lethal, is less recognized, and is still quite misunderstood: muscle wasting in cancer patients, which is prominent in pancreatic cancer patients.

Swarnali Acharyya, P... - Click to enlarge in new windowSwarnali Acharyya, PhD. Swarnali Acharyya, PhD, focuses her research on muscle wasting in cancer patients. "The key question here: what is triggering this muscle wasting and how can we stop this?"

Cachexia, as it is called formally, is often the public face of cancer, seen in patients with marked weight loss resulting in a thin, gaunt appearance. However, it can also be found in patients who gain weight, masked by fat covering the reality of its presence.


"This term was coined in the 1800s; it was prevalent even then," Acharyya told Oncology Times. "But now in 2020, more than 200 years later, there still is no cure for it because it has been very difficult to narrow down its cause. The earlier thinking was, 'It is a nutritional problem. Feed the patient and they will gain weight. Problem solved.' But that didn't happen. Even with intravenous feeding, patients still lost weight, muscle mass, and function. It turns out that it is really a muscle degradation problem of the muscle proteins. So no matter how much input there is, the output is just way more. The key question here: what is triggering this muscle wasting and how can we stop this?"


Unfortunately, many clinicians still regard cachexia as a nutritional problem and Acharyya believes it's important to diagnose cachexia correctly. While thinking in broad terms about solid tumors, metastatic cancer progresses, spreads to other organs, and kills patients.


"If the tumor takes over in vital organs-heart, lung, liver, brain, bone-that obviously impacts patient survival. But another aspect of metastatic cancer is cachexia in the muscles, where cancer is rarely found," she explained. "It's not really the tumor cells inhabiting these organs, but distantly they are probably releasing certain factors which induce this type of loss. It is a metabolic change throughout the body that is enough to kill the patient. Cancer patients with cachexia are unable to accomplish basic daily functions such as chewing food or walking."


Cause & Effect

It is believed that circulating cytokines and inflammation are at the root of the problem. However, there have been more than 130 clinical trials trying to pinpoint the cause and effect of cachexia, and all of them have failed, relates the researcher.


"There was no gain in muscle mass and muscle strength from blocking these circulating factors," Acharyya noted. "There has been some promise in animal models, but no one has been able to successfully translate it to humans."


While doing her PhD at The Ohio State University in 2002, she worked in a lab that was looking at muscle wasting from the aspect of changes in muscle cells during cancer. The Guttridge laboratory tried to find processes in the muscle that changed with time and determine how the muscle proteins were being lost.


"But once in my own lab, I wanted to look at it from the cancer aspect, especially in the context of advanced cancer when cancer cells have spread all over the body. I felt this was important because 80 percent of advanced cancer patients develop cachexia during the course of their disease progression. What from the cancer is actually triggering it? So with my husband's help, that is what we've done," Acharyya explained.


The lab has generated a lot of new animal models that can mimic the disease. By genetically engineering mouse models and using patient-derived tissues, the team was able to see the same conditions as seen in patients.


"Initially, the animal models have a primary tumor and they show some wasting. After we remove the primary tumor (mimicking surgery), the animals slowly start to show metastasis and the cachexia problem becomes apparent. The muscle loss problem occurs all over the body, not just in one group of muscles," she detailed. "It is seen in the respiratory muscles, the diaphragm, the limbs, and heart muscles. They all undergo wasting. Most patients actually die from the resulting respiratory failure and cardiac failure."


An Unexpected Trigger

The good news is the lab has found an unexpected trigger candidate: a zinc transporter known as ZIP14 (Nat Med 2018;24(6):770-781). The zinc transporter protein increases in expression in muscle cells in cancer, which ultimately destroys the muscle cells from excess zinc entry.


"In mice with cancer without this zinc transporter expressed in the muscle, there was much less zinc entry and reduced muscle wasting. But what was triggering this activation?" asked Acharyya, ready to provide the answer. "We found a couple of circulating cytokines that seemed to be inducing it, although there are probably many other triggers. So next we blocked the cytokines and we also blocked the transporter in the muscle, and we saw the exact same phenotype. In other words, if there's cancer and you block those, you see less muscle wasting. We saw that happen across cancer types, not just one."


Taking this a step further, the lab team wondered what would happen if they fed the mice excess zinc supplements. Sure enough, they started to waste more. And when the excess zinc was removed, they returned to normal.


"So we really think we can modulate the zinc levels in the diet and affect the degree of muscle wasting in a tumor-bearing state in mice," Acharyya stated. "We also figured out a connection between excess zinc and blocked muscle regeneration in cancer.


"Following an injury, muscles start to regenerate. Stem cells of muscles proliferate in response to injury, differentiate, and fuse to form mature muscles. But in cancer, this process is disturbed. The stem cells are activated, but they don't fuse to form new muscles. We saw that the zinc transporter expression increases in the muscle stem cells and excess zinc entry into these stem cells blocks muscle differentiation," she explained. "We think that if we find a drug/antibody to block this transporter and prevent excess zinc entry into muscle cells during cancer, it won't be very toxic and it could be a viable therapy in the future. My husband's biochemistry background is coming into play because he is creating antibodies to block the function of the transporter. Ultimately, if we can find a small molecule inhibitor that can block this transporter, that would be ideal."


Acharyya's lab also has a keen interest in understanding why metastatic cancer is not as responsive to therapies as primary tumors. The team is trying to determine what has changed in the metastatic cells to make them so resistant.


"Studies show that it is not necessarily the tumor cells themselves always, but in many cases, the tumor microenvironment that causes the resistance," she said. "We are looking at a particular population of immune cells, specifically B cells that make antibodies. We are trying to figure out why B cells are recruited to tumors and why they are present in drug-resistant tumors. We are trying to identify immune microenvironment interactions that may promote metastasis."


Beyond the Lab

Acharyya came to this country from her native Calcutta, India, where both of her parents were in academia. Her father was a Fulbright scholar who visited the U.S. when she was very young and, along with her mother, inspired her to pursue higher studies in the U.S. She attributes her love of research to her parents' own intellectual curiosity and willingness to let her pursue education in this country.


It seems they also nurtured in her other interests, specifically a passion for painting (particularly landscapes), which she has been doing since the second grade.


"It is something I truly love," she remarked, adding that her husband also enjoys a creative bent via wildlife photography and cooking. What she also truly enjoys is their shared passion for teaching, doing science together, and mentoring students.


"Our approaches are very different to many scientific problems, which makes it interesting to solve and also learn during the process. We are also incredibly fortunate to have excellent students and colleagues in the laboratory who bring new perspectives to important clinical problems." Acharyya and her husband are also trying to redesign the course and create a cancer progression course and a symposium, which doesn't exist now at Columbia.


Another non-lab activity for this lab-centric couple (who, incidentally, met at a breast cancer conference) is travel-both domestic and international. In addition to getting back to India about once a year, Acharyya said they have recently been to Germany and have a fall trip planned to Argentina. "Thailand is our next target destination," she added.

Lord Ganesha. Swarna... - Click to enlarge in new windowLord Ganesha. Swarnali Acharyya, PhD, spends time out of the laboratory painting. This artwork focuses on the Elephant-God (Lord Ganesha) from India in the center and some folktales on the sides.

The pair also tries to keep the lab research pipeline filled with inquisitive young minds by offering summer workshops for high school and undergraduate students who are interested in knowing more about the animal and cell culture models they use, and in working with them to gain exposure to the field of cancer progression.


All roads, it seems, lead back to the laboratory. And why not? "We have surfaced some findings that I am really very excited about," said Acharyya, before quickly adding, "but there is still a lot of work to be done."


Valerie Neff Newitt is a contributing writer.


Spotlight on Young Investigators