Metabolism and Motility: Characterizing Metabolic Changes that Lead to Metastasis.

Abstract

Cancer is an often devastating disease that affects populations throughout the world. The major cause of cancer-related death is metastasis, not the primary tumor. By understanding changes in cancer cells that allow them to locally invade and move into new tissues and organs, we may be able to identify new therapeutic targets for preventing metastasis. In this work, we studied aggressive breast cancer by examining how neoplastic cells use energy. We hypothesized that alterations in metabolism may define a switch that causes cancer cells to change their behavior from a highly proliferative state, like that of a primary tumor, to a more motile and invasive state, leading to the early steps of metastasis.

We found that inhibition of the mevalonate pathway, a metabolic pathway that makes cholesterol and isoprenoid precursors for the lipid bilayer as well as hormone precursors for signaling, leads to decreased motility and invasion in breast cancer cells. In addition, we identified an alternative mechanism of action for mevalonate pathway inhibitor, zoledronic acid.

Studying the metabolic switch from a different perspective, we found that the rare and highly aggressive inflammatory breast cancer cell line SUM149 does not undergo oxidative phosphorylation. Rather, these cells use an alternative metabolic pathway to direct acetyl-CoA out of the tricarboxylic acid cycle, thereby preventing the production of oxidative phosphorylation intermediates. This pathway may enable these cells to survive more readily in conditions of hypoxia, because oxidative phosphorylation, which consumes oxygen, would be unnecessary.

Finally, returning to our overall aim, we examined the behavioral switch between proliferation and motility directly by investigating an aggressive breast cancer cell line MDA-MB-231 in which we knocked down mitogen activated protein kinase pathway member p38gamma. This results in highly proliferative, but less motile cells. We performed unbiased metabolomic screening and found that nucleotide synthesis, NADH metabolism, and C-21 steroid hormone biosynthesis are necessary for this change in behavior. From this work, we learned how individual metabolic pathways regulate motility and invasion. Characterizing how these pathways interact to create the ideal environment to induce cancer cells to become metastatic will be the focus of discussion and future study.