Study of breast cancer metastasis upends conventional wisdom, suggesting new treatment strategy

November 12, 2015, Weill Cornell Medical College
From left: Dr. Ding Cheng Gao, Kari Fischer, Dr. Vivek Mittal. Credit: Carlos Rene Perez

Breast cancer cells do not undergo a commonly accepted transformation in order to spread to distant organs such as the lungs, Weill Cornell Medicine investigators have found in a new study. This discovery may settle a longstanding debate about how cancers spread, the investigators say, and may profoundly change the way many forms of the disease are treated.

For more than a decade, many researchers have believed that a biological process that transforms the shape of cells that line cavities, organs and blood vessels in the body was necessary for metastasis. Epithelial to mesenchymal transition, or EMT, strips away the cells' ability to hold on tightly to their neighbors, allowing them to migrate throughout the body. During fetal development, EMT provides a way for cells in the embryo to travel long distances for the generation of complex organs and bony appendages. Cancer biologists in the early '90s discovered that a subpopulation of tumor cells behaved the same way, positing that EMT gave "legs" upon which to crawl away from a tumor. But other scientists have questioned the theory, and a vigorous controversy has ensued.

In their study, published Nov. 11 in Nature, Weill Cornell Medicine investigators discovered that while EMT occurred in a small number of primary breast tumor cells, they were not involved in cancer metastasis. What's more, metastasis was derived from non-EMT cancer cells, contradicting the common theory about how cancers spread. About 90 percent of all cancer-related deaths are due to metastasis. Strikingly, the EMT status changed with the addition of chemotherapy. The recurrent lung metastases that appeared after chemotherapy treatment were from EMT tumor cells, indicating that that EMT contributes to the survival of chemoresistant tumor cells. Their findings may offer a more effective treatment strategy for and many other kinds of cancer.

"EMT has been considered cancer's Achilles heel, and now we show that this is true, but not in the way many thought," said co-senior author Dr. Vivek Mittal, an associate professor of cell and developmental biology in cardiothoracic surgery and of cell and developmental biology at Weill Cornell Medicine, director of the institution's Neuberger Berman Foundation Lung Cancer Research Center Laboratory, and a member of its Sandra and Edward Meyer Cancer Center.

"There is a substantial effort underway to develop drugs aimed at reversing the EMT process in order to halt metastasis, but our findings suggest that this approach may not work," he added. "Instead, we suggest combining chemotherapy with a drug that blocks EMT as the first treatment given to breast cancer patients—and likely others with cancer as well."

Study of breast cancer metastasis upends conventional wisdom, suggesting new treatment strategy
The top panel of this image shows breast cancer cells designed to change from red to green when they transition from epithelial to mesenchymal through the EMT. The bottom panel shows breast cancer cells in primary tumors, which progress to generate red metastatic nodules in the lung. Chemotherapy ablates the red nodules and generates green EMT nodules. Credit: Mittal lab
"Our study clarified a longstanding question in the field by finding that lung metastases mainly arise from tumor cells that have not undergone EMT," said co-senior author Dr. Ding Cheng Gao, an assistant professor of cell and developmental biology in cardiothoracic surgery and of cell and developmental biology, and a member of the Meyer Cancer Center at Weill Cornell Medicine. "However, the EMT tumor cells appear more resistant to chemotherapy, suggesting that the combination of anti-EMT approach and traditional chemotherapy is a better way for combating the deadly metastatic disease."

For their study, the Weill Cornell Medicine investigators and their collaborators at Columbia University, Houston Methodist Research Institute, and Soonchunhyang University in South Korea, developed a new technique called EMT cell lineage tracing to understand the role of EMT in breast cancer. The system, which took three years to develop, tracks individual in preclinical models of metastatic breast cancer. The investigators engineered the original cells to emit a red fluorescence. While EMT occurs, the cancer cells switched from red to green fluorescence.

"As would be expected, we found that within a predominantly epithelial primary tumor, a small portion of tumor cells had undergone EMT," Dr. Mittal said.

But strikingly they also found that cells that metastasized to the lung were red, not green. "This finding was unexpected and suggested that the general notion that EMT is important for generating metastasis was not correct," he said.

To confirm their discovery, the researchers blocked EMT with an inhibitor and found it had no effect on metastasis to the lungs. Then they investigated what happened after the mice received chemotherapy. The chemo treatment efficiently eliminated the glowing red cells—including those in the lungs—but not the green EMT tumor cells. Researchers then observed green metastatic lesions in the lung, which are derived from the EMT cancer cells.

This schematic shows epithelial (red) and mesenchymal (green) cancer cells in primary breast tumors. These tumors metastasize to the lungs to form red nodules, indicating EMT does not generate metastasis (left), but following chemotherapy treatment, green EMT nodules appear (middle), which are chemoresistant (right). Combination treatment with EMT blocker and chemotherapy impairs all metastatic nodules, thereby providing a novel therapeutic approach. Credit: Mittal lab
"This can explain why patients initially respond to chemotherapy, only to find later that the cancer has spread because of chemoresistant EMT ," Dr. Mittal said.

Researchers then tested a therapy that combines chemotherapy with their experimental EMT blocker and found that no metastasis—and no chemoresistance—occurred in the mice.

"The EMT was a wonderfully compelling explanation for how metastasis could occur, and we certainly did not expect these findings," said first author Kari Fischer, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences. "Hopefully this will redirect efforts toward other explanations for how epithelial cancer cells move. In the meantime, we have made very exciting inroads towards discovering the root of chemoresistance."

Drs. Gao and Mittal are now using their EMT lineage tracing system as a platform to develop and test combination therapies that can be used in patients that will eliminate both epithelial and drug-resistant EMT cancer cells. The translation of their findings could aid the 90 percent of late stage metastatic patients with treatment-refractory disease.

Explore further: Study reveals why chemotherapy may be compromised in patients with pancreatic cancer

More information: Kari R. Fischer et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance, Nature (2015). DOI: 10.1038/nature15748

Related Stories

Study reveals why chemotherapy may be compromised in patients with pancreatic cancer

November 11, 2015
A study at The University of Texas MD Anderson Cancer Center may explain why chemotherapy drugs such as gemcitabine are not effective for many pancreatic cancer patients, and perhaps point to new approaches to treatment including ...

New breast cancer stem cell findings explain how cancer spreads

January 14, 2014
Breast cancer stem cells exist in two different states and each state plays a role in how cancer spreads, according to an international collaboration of researchers. Their finding sheds new light on the process that makes ...

Study finds switch that lets early lung cancer grow unchecked

July 11, 2012
Cellular change thought to happen only in late-stage cancers to help tumors spread also occurs in early-stage lung cancer as a way to bypass growth controls, say researchers at Mayo Clinic in Florida. The finding, reported ...

New evidence that cancer cells change while moving throughout body

August 12, 2013
For the majority of cancer patients, it's not the primary tumor that is deadly, but the spread or "metastasis" of cancer cells from the primary tumor to secondary locations throughout the body that is the problem. That's ...

Study helps resolve debate about how tumors spread

November 29, 2012
A team of scientists, led by researchers at the University of California, San Diego School of Medicine, has shown for the first time how cancer cells control the ON/OFF switch of a program used by developing embryos to effectively ...

Transition in cell type parallels treatment response, disease progression in breast cancer

January 31, 2013
A process that normally occurs in developing embryos – the changing of one basic cell type into another – has also been suspected of playing a role in cancer metastasis. Now a study from Massachusetts General Hospital ...

Recommended for you

New 'SLICE' tool can massively expand immune system's cancer-fighting repertoire

November 15, 2018
Immunotherapy can cure some cancers that until fairly recently were considered fatal. In addition to developing drugs that boost the immune system's cancer-fighting abilities, scientists are becoming expert at manipulating ...

Anti-malaria drugs have shown promise in treating cancer, and now researchers know why

November 15, 2018
Anti-malaria drugs known as chloroquines have been repurposed to treat cancer for decades, but until now no one knew exactly what the chloroquines were targeting when they attack a tumor. Now, researchers from the Abramson ...

Researchers identify a mechanism that fuels cancer cells' growth

November 14, 2018
Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose, which is key to their survival and promotes ...

A new approach to detecting cancer earlier from blood tests: study

November 14, 2018
Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy", epigenetic alterations and machine learning to develop a blood test to detect and classify ...

New antibody breakthrough to lead the fight against cancer

November 14, 2018
Scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancer's defence against the body's immune system.

Photoacoustic imaging may help doctors detect ovarian tumors earlier

November 14, 2018
Ovarian cancer claims the lives of more than 14,000 in the U.S. each year, ranking fifth among cancer deaths in women. A multidisciplinary team at Washington University in St. Louis has found an innovative way to use sound ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.