A new University of Kentucky Markey Cancer Center study reveals more about changes that happen to cancer cells when they metastasize and identifies a promising target for the treatment of metastatic breast cancer.

Metastasis is when cancer cells spread from the primary tumor to surrounding tissues and distant organs in the body and is the primary cause for breast cancer mortality. Cancer cells’ plasticity, or their ability to change and adapt, is critical for progression to metastatic cancer.

The research, published in PNAS May 8, shows a metabolite called succinate plays a role in enhancing cancer cell plasticity and identifies an enzyme called PLOD2 as a regulator of succinate during breast cancer progression.

“The results reveal a previously unidentified function of succinate and its role in breast cancer metastasis, filling a critical gap in our knowledge regarding how changes in metabolites promote cancer cell plasticity,” said Ren Xu, Ph.D., the study’s principal investigator and a professor in the UK College of Medicine’s Department of Pharmacology and Nutritional Sciences.

In collaboration with Andrew N. Lane, Ph.D., professor in the College of Medicine’s Department of Toxicology and Cancer Biology and co-director of the Center for Environmental and Systems Biochemistry, Xu’s team studied metabolic reprogramming in mammary epithelial cells during epithelial mesenchymal transition (EMT), a biologic process that mobilizes cancer cells.

The results also suggest targeting PLOD2 could be a promising strategy to suppress breast cancer metastasis and drug resistance.

PLOD2 expression during EMT elevated succinate levels in breast cancer cells, while PLOD2 inhibition reduced succinate levels and inhibited cancer cell plasticity.

“As PLOD2 is a druggable target, these findings could pave the way for the development of new therapies to stop cancer progression,” said Xu.

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R01CA207772 and R01CA215095. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.