Metabolic vulnerabilities could be new targets for metastatic breast cancer

Metabolic differences could explain why some metastatic breast cancer cells rapidly generate tumors after migrating from primary tumors to the brain, while others linger for months or years before forming these secondary tumors, UT Southwestern scientists report in a new study. The findings, published in Cell Metabolism, highlight metabolic vulnerabilities in malignant cells that could eventually lead to new cancer therapies.

"Brain metastasis is a major problem for breast cancer patients, and most of the treatments that we have are not that effective. We have identified unique features of metastatic breast cancer cells that could serve as new targets," said Srinivas Malladi, Ph.D., Assistant Professor of Pathology and member of the Harold C. Simmons Comprehensive Cancer Center,  who co-led the study with Pravat Kumar Parida, Ph.D., a postdoctoral fellow in the Malladi lab.

The brain is a common site for breast cancer metastasis, particularly for patients with a subtype of this disease known as HER2+. About half of patients with HER2+ breast cancers develop secondary tumors at some point after their primary tumor is diagnosed, Dr. Malladi explained, a phenomenon known as metachronous brain metastasis (M-BM). Synchronous brain metastasis (S-BM), when secondary brain tumors are diagnosed at the same time as the primary breast tumor, are rarer - but patients with S-BM have a far worse prognosis, with a median overall survival of just six months after diagnosis. HER2+ breast cancer patients with latent brain metastatic cells (Lat) are asymptomatic and likely to develop M-BM over variable lengths of time.

Using an animal model developed in the Malladi lab, Drs. Malladi, Parida and their colleagues found significant differences in the metabolism of these different types of brain metastatic cells. For example, while S-BM cells used glucose as a primary fuel source, M-BM and Lat cells used a related sugar called glutamine. Also, Lat cells secreted less lactate, a form of lactic acid, than M-BM and S-BM cells. Lactate helps M-BM and S-BM cells to evade innate immune surveillance and hence can promote tumor survival.

Additionally, the researchers discovered higher amounts of a protein known as xCT, which mediates oxidative stress, in the M-BM and Lat cells compared to S-BM. Stemming the activity of this protein using genetic techniques and chemical inhibitors significantly reduced the metastatic activity of M-BM and Lat cells and made them more vulnerable to drugs that target HER2+ cells.

Dr. Malladi noted that the differences identified in the study suggest potential targets to attack brain metastasis in breast cancers and potentially other types of malignancies. Because an xCT inhibitor is already being tested in clinical trials for multiple myeloma, he added, its use could represent a particularly promising strategy for attacking metabolic vulnerabilities of brain metastases.

The Simmons Cancer Center, the only National Cancer Institute-designated comprehensive cancer center in North Texas, is ranked among the top 25 cancer centers in the nation by U.S. News & World Report. UT Southwestern, home of the Peter O'Donnell Jr. Brain Institute, is also ranked among the top 20 hospitals for neurology and neurological surgery by U.S. News.

Other UTSW scientists who contributed to this study include Mauricio Marquez-Palencia, Vidhya Nair, Akash K. Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ambar Cajigas, Vamsidhara Vemireddy, Paula I. Gonzalez-Ericsson, Melinda E. Sanders, Bret C. Mobley, Kenneth Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert M. Bachoo, Carlos L. Arteaga, Ariella B. Hanker, and Ralph J. DeBerardinis. Disclosures are available in the paper.

The research was funded by grants from the Cancer Prevention and Research Institute of Texas (RP210041and RR170003), the National Science Foundation (2019281049), the National Cancer Institute, (R35CA22044901), the American Cancer Society (RSG-20-47-01-CSM), and METAvivor (GAA202106-0027).

Dr. Arteaga, Director of the Simmons Cancer Center, holds the Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. Dr. Bachoo, an Associate Professor of Neurology, holds the Miller Family Professorship in Neuro-Oncology. Dr. DeBerardinis, Chief of the Division of Pediatric Genetics and Metabolism, holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics, and is a Sowell Family Scholar in Medical Research at UTSW.

About UT Southwestern Medical Center

UT Southwestern, one of the nation's premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.