Extracellular Matrix Stiffness Regulates Metabolic State In Metastatic, But Not Quiescent, Breast Carcinoma Cells

Increased breast density is associated with a 4-6 fold increased risk of developing breast cancer, and is associated with an increase in deposition of extracellular matrix (ECM) proteins, most abundantly collagen I. Collagen, like other ECM proteins, plays a structural role fundamental to tissue organization. High levels of collagen deposition correspond with a stiffer ECM, which is emerging as an important regulator of cell proliferation and tumor progression. Our previously reported microarray implicated changes in mammary epithelial cell metabolism in response to increased matrix stiffness, consistent with the expanding role of the ECM in tumor cell signaling. Here we report that increased matrix stiffness regulates the expression of pyruvate dehydrogenase kinase 1, a key regulator between lactic acid production and pyruvate entry into the mitochondria, in highly metastatic 4T1 breast carcinoma cells. Interestingly, we do not observe this same metabolic regulation in quiescent (dormant) 4T07 tumor cells of the same lineage. These alterations in protein expression correlated to changes in cellular NADH metabolism observed by several independent approaches, including metabolic flux analysis and quantitative imaging fluorescence lifetime microscopy. Thus, we find that alterations in collagen stiffness cause metabolic shifts between oxidative phosphorylation and aerobic glycolysis in highly metastatic cells, but not in quiescent cells. These findings identify stiffness of the ECM as an important regulator of metabolic state, and further identify quiescence as a dominant trait that is not overcome by ECM stiffness. Citation Format: Brett A. Morris, Brian Burkel, Suzanne Ponik, Kevin Eliceiri, Julio Aguirre-Ghiso, John Condeelis, James Castracane, Patricia J. Keely. Extracellular matrix stiffness regulates metabolic state in metastatic, but not quiescent, breast carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2015-332