title: 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.
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, United States.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Morris
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, United States; Department of Biomedical Engineering, University of Wisconsin-Madison, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Burkel
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, United States. Electronic address: ponik@wisc.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Ponik
authors.affiliation: Wisconsin Institute for Discovery and Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, United States; Morgridge Institute for Research, Madison, WI, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Dept. of Anatomy & Structural Biology, Albert Einstein College of Medicine, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, United States; Department of Otolaryngology, Tisch Cancer Institute, Mount Sinai School of Medicine, United States; Department of Oncological Sciences, Tisch Cancer Institute, Mount Sinai School of Medicine, United States; Black Family Stem Cell Institute, Mount Sinai School of Medicine, United States.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.affiliation: Colleges of Nanoscale Science and Engineering (CNSE), SUNY Polytechnic Institute, United States.
authors.forename: James
authors.initials: J
authors.lastname: Castracane
authors.affiliation: Wisconsin Institute for Discovery and Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, United States; Morgridge Institute for Research, Madison, WI, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.affiliation: Department of Cell and Regenerative Biology, School of Medicine and Public Health, United States; Paul C. Carbone Cancer Center, University of Wisconsin-Madison, United States.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002952:Citric Acid Cycle; D003094:Collagen / Q000378:metabolism*; D004734:Energy Metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D017382:Reactive Oxygen Species; D005973:Glutamine; D003094:Collagen; D005947:Glucose; D010100:Oxygen
keywords: Breast cancer; Collagen; Matrix density; Metabolism