Researchers seeking ways to treat breast cancer focus on cellular changes as disease spreads to brain
DALLAS – Mitochondria that power cellular activity fragment and change shape in breast cancer cells that migrate to the brain, an adaptation that appears necessary for the cells to survive, UT Southwestern Medical Center researchers report in a new study. The findings, published in Nature Cancer, could lead to new ways to prevent brain metastases, or the spread of cells from primary tumors to the brain.
Srinivas Malladi, Ph.D., is Assistant Professor of Pathology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.
“Through mitochondrial plasticity, these cancer cells undergo metabolic reprogramming that aids their survival in the brain niche that otherwise would not be available to them. Exploiting this vulnerability could offer a way to prevent brain metastases,” said study leader Srinivas Malladi, Ph.D., Assistant Professor of Pathology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center.
Metastatic cancer, which is treated as stage IV cancer, is responsible for the majority of cancer deaths.
The Malladi lab focuses on understanding how cells that escape from a primary tumor can live in different locations in the body, often for years, before emerging as metastatic cancer. Using breast cancer, a disease that commonly metastasizes to the brain, as a model, Dr. Malladi and his colleagues discovered that cancer cells that migrate to the brain reprogram their metabolism to depend on fatty acids rather than carbohydrates as a main energy source.
This switch is necessary to survive in the brain, which is a completely different environment, Dr. Malladi explained. But how the cells accomplish this metabolic switch was unclear.
To answer this question, Dr. Malladi and his team isolated latent metastatic (Lat) cells – cancer cells that had migrated from the primary tumor but had not begun actively forming new tumors – from the brains of mouse models. They observed that these Lat cells have distinctly shaped “punctate,” or dot-like, mitochondria compared to the primary tumor cells with elongated tubular mitochondria. Moreover, the Lat cells readily used fatty acids. This suggested that the mitochondrial shape change or plasticity was necessary for fatty acid metabolism.
Further experiments showed that the fragmentation was driven by an increase in a protein known to be involved in mitochondrial fission called dynamin-related protein 1 (DRP1). When the researchers used a genetic technique to decrease the amount of DRP1, the Lat cells’ mitochondria regained their tubular shape and lost the ability to metabolize fatty acids. Similarly, when they used a chemical that inhibited DRP1, Lat cells residing in mouse brains formed fewer metastases and were significantly less likely to survive.
A separate examination of metastatic tumors that formed in breast cancer patients showed that a phosphorylated form of DRP1 was elevated, suggesting that this phenomenon occurs in humans as well, Dr. Malladi said.
He and his colleagues plan to test DRP1 inhibitors to determine whether they might prevent, slow, or reverse metastatic disease, an important next step toward developing a treatment.
Other UTSW researchers who contributed to this study include Pravat Kumar Parida, Ph.D., Postdoctoral Researcher; Mauricio Marquez-Palencia, student in the Graduate School of Biomedical Sciences; Suvranil Ghosh, Ph.D., Postdoctoral Researcher; Nitin Khandelwal, Ph.D., Instructor; Kangsan Kim, Ph.D., Senior Research Associate; Hieu Vu, Ph.D., Senior Research Scientist; Lauren G. Zacharias, M.S., Children’s Medical Center Research Institute (CRI) Metabolomics Facility Manager; Jeffrey G. McDonald, Ph.D., Professor of Molecular Genetics; Andrew Lemoff, Ph.D., Assistant Professor of Biochemistry; Yan Peng, M.D., Ph.D., Professor of Pathology; Cheryl Lewis, Ph.D., Associate Professor of Pathology; Gonçalo Dias do Vale, Ph.D., Assistant Professor of Molecular Genetics; Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center and Professor of Internal Medicine; Ariella B. Hanker, Ph.D., Assistant Professor of Internal Medicine; and Ralph J. DeBerardinis, M.D., Ph.D., a Professor at CRI and of Pediatrics.
This research was funded by grants from the Cancer Prevention and Research Institute of Texas (RP210041, RR170003), the National Science Foundation (2019281049), the National Cancer Institute (R35CA22044901), a Cancer Center Support Grant (P30 CA142543), the American Cancer Society (RSG-20-47-01-CSM), METAvivor (GAA202106-0027), a Susan G. Komen Career Catalyst Grant (CCR22902470), and an SCCC Cancer and Obesity Translational Pilot Program Grant and Breast Cancer-Bone initiative from Charles Y.C. Pak Foundation grants.
Financial interest disclosures for the authors may be found in the study.
About CRI
CRI is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology, and metabolism. For more information, visit cri.utsw.edu. To support CRI, visit give.childrens.com/about-us/why-help/cri/