title: Mechanistic modeling of the effects of myoferlin on tumor cell invasion.
abstract: Myoferlin (MYOF) is a member of the evolutionarily conserved ferlin family of proteins, noted for their role in a variety of membrane processes, including endocytosis, repair, and vesicular transport. Notably, ferlins are implicated in Caenorhabditis elegans sperm motility (Fer-1), mammalian skeletal muscle development and repair (MYOF and dysferlin), and presynaptic transmission in the auditory system (otoferlin). In this paper, we demonstrate that MYOF plays a previously unrecognized role in cancer cell invasion, using a combination of mathematical modeling and in vitro experiments. Using a real-time impedance-based invasion assay (xCELLigence), we have shown that lentiviral-based knockdown of MYOF significantly reduced invasion of MDA-MB-231 breast cancer cells in Matrigel bioassays. Based on these experimental data, we developed a partial differential equation model of MYOF effects on cancer cell invasion, which we used to generate mechanistic hypotheses. The mathematical model predictions revealed that matrix metalloproteinases (MMPs) may play a key role in modulating this invasive property, which was supported by experimental data using quantitative RT-PCR screens. These results suggest that MYOF may be a promising target for biomarkers or drug target for metastatic cancer diagnosis and therapy, perhaps mediated through MMPs.
authors.affiliation: Mathematical Biosciences Institute, Ohio State University, Columbus, OH 43210, USA. meisenberg@mbi.osu.edu
authors.forename: Marisa C
authors.initials: MC
authors.lastname: Eisenberg
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Kim
authors.forename: Ruth
authors.initials: R
authors.lastname: Li
authors.forename: William E
authors.initials: WE
authors.lastname: Ackerman
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kniss
authors.forename: Avner
authors.initials: A
authors.lastname: Friedman
mesh_terms: D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D003198:Computer Simulation; D004338:Drug Combinations; D004705:Endocytosis; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D002135:Calcium-Binding Proteins; D004338:Drug Combinations; D007797:Laminin; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases