Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells

Abstract

Increased breast density attributed to collagen I deposition is associated with a 4–6 fold increased risk of developing breast cancer. Here, we assessed cellular metabolic reprogramming of mammary carcinoma cells in response to increased collagen matrix density using an in vitro 3D model. Our initial observations demonstrated changes in functional metabolism in both normal mammary epithelial cells and mammary carcinoma cells in response to changes in matrix density. Further, mammary carcinoma cells grown in high density collagen matrices displayed decreased oxygen consumption and glucose metabolism via the tricarboxylic acid (TCA) cycle compared to cells cultured in low density matrices. Despite decreased glucose entry into the TCA cycle, levels of glucose uptake, cell viability, and ROS were not different between high and low density matrices. Interestingly, under high density conditions the contribution of glutamine as a fuel source to drive the TCA cycle was significantly enhanced. These alterations in functional metabolism mirrored significant changes in the expression of metabolic genes involved in glycolysis, oxidative phosphorylation, and the serine synthesis pathway. This study highlights the broad importance of the collagen microenvironment to cellular expression profiles, and shows that changes in density of the collagen microenvironment can modulate metabolic shifts of cancer cells.

Collagen stiffness modulates MDA-MB231 cell metabolism through adhesion-mediated contractility

“…This correlates with previous studies in that breast cancer cells have increased migration and aggressiveness within stiffer collagen matrices (Haage and Schneider, 2014;Levental et al, 2009;Paszek et al, 2005). In addition, cancer cells undergo aerobic glycolysis for energy production, thus increased substrate stiffness could be a contributor to the metabolic shift towards glycolysis (Liberti and Locasale, 2016;Morris et al, 2016). The ECM plays a key role in the cancer cell's mechanosensing pathway through integrin signaling, and there is increasing evidence that this regulates cell migration and matrix degradation (Alexander et al, 2008;Beaty et al, 2013;Chiu et al, 2013;Van Horssen et al, 2013).…”

“…Downstream of GLY are intermediates of the tricarboxyl acid cycle, such as citrate, which allows for synthesis of lipids, proteins and nucleic acids, a demand for highly proliferating cells (DeBerardinis et al, 2008). There is also fatty acid synthesis through citrate which is shown to correlate with the formation of invadopodia, which are actin rich protrusions used for matrix invasion (Gould and Courtneidge, 2014;Morris et al, 2016;Scott et al, 2012). In addition, the pentose phosphate pathway could further increase the GLY and fraction of free NADH.…”

Collagen Production and Niche Engineering: A Novel Strategy for Cancer Cells to Survive Acidosis and Evolve

“…Collagens are major proteins of the ECM. The unique mechanical properties of collagens are mainly controlled by its structure and density that affects ECM induced tumor growth, migration, and metastasis (25). Increased deposition and re-organization of collagens, fibronectin, and proteoglycans is observed in the transition from DCIS to locally invasive disease and also in later stages and metastasis (26, 27).…”

Two‐photon fluorescence lifetime imaging of intrinsic NADH in three‐dimensional tumor models

“…In addition to the wealth of information regarding the biochemistry of ECM signaling, the mechanical aspects of matrix density and stiffness have emerged as critical factors regulating cell behavior (14)(15)(16)(17)(18)(19). In addition to the wealth of information regarding the biochemistry of ECM signaling, the mechanical aspects of matrix density and stiffness have emerged as critical factors regulating cell behavior (14)(15)(16)(17)(18)(19).…”

“…Tumor and stromal cell interactions occur within, and are strongly influenced by, the physical and chemical environment of the extracellular matrix (ECM). In addition to the wealth of information regarding the biochemistry of ECM signaling, the mechanical aspects of matrix density and stiffness have emerged as critical factors regulating cell behavior (14)(15)(16)(17)(18)(19). Although it is well known that increased breast tissue stiffness is associated with breast cancer malignancy (17)(18)(19), the effects of ECM rigidity on cancer cell metabolism are still relatively unexplored.…”