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| A microscope image of a breast cancer tumor (blue) and its surrounding microenvironment in a mouse model. Image Credit: Joseph Szulczewski, David Inman, Kevin Eliceiri, and Patricia Keely/University of Wisconsin/National Institutes of Health |
Scientists have gained new insights into how nutrient availability in different organs affects the spread, or metastasis, of breast cancer throughout the body.
In a study in mice jointly led by researchers at Harvard Medical School, Massachusetts General Hospital, and MIT, the team found that no single nutrient explains why breast cancer grows in one organ and not another. Instead, multiple nutrients and cancer cell characteristics work together to shape the spread of the disease.
The team also discovered that breast cancer cells require the nutrient purine to metastasize, regardless of their location or other nutrients available.
Because the research was done in mice, the findings will need to be replicated in humans to confirm that the process is conserved across species.
The research deepens understanding of cancer metastasis and is an important step toward further refining treatments for breast cancer.
“Long term, we hope this kind of work will help personalize cancer therapy based on where tumors are likely to spread and how they feed themselves once they arrive,” said co-senior author Rakesh Jain, the HMS A. Werk Cook Professor of Radiation Oncology at Mass General.
An open question for a common cancer
Despite considerable treatment advances in recent years, breast cancer remains the second most common cancer and the second leading cause of cancer death for U.S. women.
One challenge is that scientists still don’t fully understand how breast cancer metastasizes, including why tumors grow better in some organs than others.
Jain and colleagues wanted to know if certain nutrients are more important than others for enabling this differential growth across organs.
In their new paper, the researchers first assessed the “nutrient landscape” that cancer cells experience by measuring the levels of more than 100 nutrients in the brain, blood plasma, and organs of mice. Then, they genetically modified breast cancer cells to stop making specific nutrients such as serine, arginine, or purines, and injected the nutrient-limited cancer cells into the mice to see where they grew.
“This allowed us to test whether cancer cells fail to grow if they can’t make a nutrient that is missing in a specific organ,” Jain explained. “For instance, if a tumor can’t make serine and the brain is low in serine, does that prevent metastasis to the brain?”
Contrary to what they had hoped, the team found that patterns of metastasis could not be fully explained by the presence or absence of any single nutrient. For example, some nutrients like purines were essential for tumor growth across organs, while others like serine or arginine had variable effects based on the organ and type of cancer cell.
Moreover, even when a nutrient was lacking in a tissue, tumors could still grow by finding other ways to adapt, such as salvaging nutrients from nearby cells.
New information opens up new possibilities
“This study shows that cancer’s ability to spread isn’t dictated by a single missing nutrient but instead by a complex mix of cell-intrinsic traits and the local environment,” Jain said.
However, the findings still provide important insights into cancer biology and treatment efforts.
The team’s discovery that purine synthesis is a universal requirement for breast cancer metastasis could point to potential therapeutic targets that might help prevent or treat metastases more broadly across tissues.
The results also challenge the notion that metastasis in breast cancer can be halted by targeting a single nutrient pathway. Instead, Jain said, researchers should take a more holistic approach by considering the combinations of nutrients that are available, genetic vulnerabilities in cancer cells, and how the cells interact with surrounding cells.
Now, the researchers are interested in exploring whether combinations of therapies — including metabolic inhibitors — can selectively block tumor growth in certain organs. They also want to better understand the strategies that cancer cells use to adapt to nutrient-limited environments. Finally, they would like to expand their research to additional cancer types.
Published in journal: Nature
Title: Nutrient requirements of organ-specific metastasis in breast cancer
Authors: Keene L. Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C. Steinbuch, Muhammad Bin Munim, Diya L. Ramesh, Sophie E. Honeder, Ashwin S. Kumar, Michelle Wu, Jacob A. Hansen, Anna Shevzov-Zebrun, Edrees H. Rashan, Kian M. Eghbalian, Sharanya Sivanand, Anna M. Barbeau, Lisa M. Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E. Trojan, Millenia Waite, Tenzin Kunchok, Mayu A. Nakano, Florian Gourgue, Gino B. Ferraro, Brian T. Do, Virginia Spanoudaki, Francisco J. Sánchez-Rivera, Xin Jin, George M. Church, Rakesh K. Jain, and Matthew G. Vander Heiden
Source/Credit: Harvard Medical School
Reference Number: ongy011026_01
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