NIH Record - National Institutes of Health

When Dead Cells Talk

NCI Investigator Discovers Signals that Spur Metastatic Cancer

Dr. Li Yang
Dr. Li Yang

One of the toughest challenges in cancer therapy is treating a relapse, when cancer cells become more stubborn and resistant, and the prognosis more precarious. 

Earlier this year, Dr. Li Yang and her lab colleagues at the National Cancer Institute discovered a mechanism that may underlie cancer relapse. They found that dying cancer cells emit signals that can trigger the growth of nearby cancer cells.

The implications are vast, and she urges the cancer research community to follow up. 

“We need an effort to investigate how dying cancer cells can also be a problem for the patient,” said Yang, senior investigator in NCI’s Laboratory of Cancer Biology and Genetics. “Our studies show there’s an unexpected side to the story of killing tumor cells, and we need to be aware.”

The Bursting Balloon

Two young researchers in white lab coats pose together in the lab.
NCI postdoc Dr. Woo Yong Park (l) and doctoral student Just Gray were integral to the discovery.

It was somewhat of an accidental discovery, Yang recalled. “It was in the back of our minds that dying cancer cells are interesting by themselves,” she said. Many tumor cells die naturally in the body—during circulation or in a hostile immune microenvironment—and many more die during cancer treatment. But treatment rarely kills all malignant cells. Some survive, hide and stay dormant, then evolve and resurface, tougher than before, and often resistant to therapy. 

“My lab became interested in the epigenetic [how the environment influences genes and cells] component of cancer cells because we believe that understanding these epigenetic changes may provide the answer for how cancer cells change when challenged with treatment and how they create diversity between each other.”

In the lab, her team discovered an epigenetic modifier called PAD4, which they found modifies chromatin—protein-encased strands of DNA. 

“We found that dying cancer cells modify their chromatin,” Yang said. “The chromatin becomes expanded and then bursts. When they burst, they’re expunging out their contents.”

Image
An image shows cancer cells and the expulsion of cell contents in the right panel.
The 4T1 breast cancer cells were treated with an apoptosis-inducing drug. beta-actin (red) indicating the cell membrane, CitH3 (green) indicating chromatin, DNA (blue) indicating nuclei. The expelled chromatin is evident (left panel), enlarged in the white dotted lines (middle panels). The chromatin filament spread far (right panel).

Photo:  Yang lab

She further explained, “Imagine the cell as a balloon filled with things. When it expands beyond its limits, it bursts. Then all of the stuff inside—the nuclei, chromatin, DNA, proteins—gets spread out, far away.”

This was the start of a groundbreaking discovery. What they found surprised them.

Cancer’s Last Words 

Light and dark purple blobs with strings of yellow and orange running across.
Cancer cells that die via apoptosis (dark purple structures) expel their nuclear contents (orange and yellow strings) to spur metastasis and growth of living cancer cells (small light blue structures).

Upon further study, “We found out that the dying tumor cells have a way to support their community,” Yang said. “Perhaps they’re not dying in vain. In their death, they communicate to the surviving cancerous cells, ensuring the community’s survival.”

That was an unexpected revelation. They observed dying cancer cells sending signals to surviving cells, making them more resistant and enabling them to spread. “Cancer cells don’t act alone. Rather, they have quite a sophisticated network of communication,” she said. 

Yang’s lab then traced these effects to a molecule, chromatin-bound S100a4, a factor that can stimulate the outgrowth of the living cancer cells. Is this mechanism of last words, of chromatin releasing from dying tumor cells, responsible for cancer relapse? This opens up an untapped avenue for exploration, toward reducing the chances of cancer recurring after treatment.

“Our investigations have found a molecular pathway containing key components that can be targeted therapeutically so that the cancer cells will not leave out the traces of chromatin that promote metastatic outgrowth,” she said. Building on this research, it might be possible to interrupt the conversation, to prevent dying cancer cells from sending the signals that provoke the spread of remaining cancer cells.

Yang recommends further study toward potential clinical trials. “The importance of our discovery goes beyond what we discovered. We hope that fellow cancer researchers, including principal investigators and young researchers, will join this effort and look into this uncovered area” that could identify new opportunities for cancer treatment and ultimately save lives.  

The Scientist Behind the Discovery

Dr. Li Yang
Dr. Li Yang

It’s never too late to follow one’s aspirations, and Yang’s journey to becoming an NCI senior investigator embodies that mantra.

Yang was born and raised in Sichuan province in China. As a child, she dreamed about making scientific discoveries. “When I was 12 years old, my father gave me a book about Madame Curie’s discovery of radium and I always dreamed of being just like her.”

After earning her undergraduate and master’s degrees in China, she emigrated to Raleigh, N.C. For years, she worked as a research technician at North Carolina State University, Duke and later Vanderbilt, where she focused on raising her two young children. 

“Many women get their careers established first. I had my babies first,” Yang said. 

While she prioritized motherhood, at the same time, she was becoming increasingly bored. Her husband, a professor at Vanderbilt, suggested she go back to school to pursue her doctorate.

“My husband said, ‘I know you want intellectual challenges and need to satisfy your curiosity. I know your mind is wanting more,’” said Yang. She decided to survey a class at Vanderbilt. 

“When I sat in on a class, I realized how much I loved it,” she said. “I loved all of the new intellectual challenges—even taking the tests.” She soon enrolled in the Ph.D. program in cancer biology.

Each day, Yang went to work or class and came home to care for her kids, who were 2 and 9 when she started her graduate studies. “I would get up around 1 or 2 in the morning to finish school coursework until about 4 or 5 a.m.,” she said. After a couple hours of sleep, she would resume her daily activities.

“I was exhausted. But it was my time, and I was using it to do something I love,” she said. “As women, we are good at adapting. The experience we have as mothers, as a family, as major contributors, we have ways to deal with stress and adapt to many different situations.”

In graduate school, Yang studied the role of the COX-2 pathway in regulation, immune response and tumor progression and how host myeloid cells contribute to tumor blood vessel formation. During her studies, she relished the opportunity to do a short stay in Japan, collaborating with a professor at Kyoto University on her dissertation project. “I learned so much about how people do science there and I enjoyed learning about Japanese culture,” she said.

After receiving her Ph.D. and completing postdoctoral work on TGFbeta signaling in breast cancer progression at Vanderbilt, Yang came to work at NCI in 2009. 

“NCI was such a great fit, regardless of my different experience,” she said. “I was much older than other applicants, but they loved the way I do science. It’s a good opportunity for me to [have access] to NIH and NCI resources, intellectual as well as technology resources. I was very lucky to come here as a researcher.”—Dana Talesnik

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