At a glance
Researchers found in mice that multiple nutrients and cancer cell characteristics work together to control the spread of breast cancer to other organs.
The team discovered that breast cancer cells require the nutrient purine to metastasize, regardless of their location.
The findings illuminate the process of cancer metastasis and could lead to more personalized therapies for breast cancer.
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.
The findings published Jan. 7 in Nature.
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.
Adapted from a Mass General Brigham news article.
Authorship, funding, disclosures
Additional authors on the paper include co-senior authors George Church and Matthew Vander Heiden, co-first authors Keene L. Abbott, Sonu Subudhi, and Raphael Ferreira, as well as 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, and Xin Jin.
The research was supported by the National Institutes of Health (grants R01CA259253, F31CA271787, T32GM007287, U01CA224348, R01CA208205, R01NS118929, U01CA261842, R35CA242379), the Koch Institute (Cancer Center Support Grant P30CA014051), the Koch Institute/Dana-Farber Harvard Cancer Center Bridge Project, the National Science Foundation (grant DGE-1122374), the MGH ECOR FMD fellowship grant (2022A018897), the Knut and Alice Wallenberg Foundation (KAW 2019.0581), the Ludwig Center at MIT, the Austrian Agency for Education and Internationalisation (Marietta Blau Grant), the Damon Runyon Cancer Research Foundation (DRG-2367-19), a Boehringer Ingelheim Fonds MD fellowship, the Aging and Longevity-Related Research Fund and EGL Charitable Foundation, a Howard Hughes Medical Institute (HHMI) Medical Research Fellowship, Key R&D Program of Zhejiang (2024SSYS0034), the Ludwig Center at Harvard, the Nile Albright Research Foundation, the National Foundation for Cancer Research, and Jane’s Trust Foundation.
Ferreira consulted for Lime Therapeutics during this study, unrelated to the work presented. Church is a cofounder of Editas Medicine and has other financial interests. Jain received consultant/science advisory board fees from DynamiCure, SPARC, and SynDevRx; owns equity in Accurius Theraputics, Enlight, and SynDevRx; served on the board of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants from Boehringer Ingelheim and Sanofi; no funding or reagents from these organizations were used in the study. Vander Heiden discloses that he is or was a scientific advisor for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Pretzel Therapeutics, Lime Therapeutics, Faeth Therapeutics, Droia Ventures, MPM Capital, and Auron Therapeutics.
