Mechanistic modeling of the effects of myoferlin on tumor cell invasion

Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20078-83. doi: 10.1073/pnas.1116327108. Epub 2011 Nov 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calcium-Binding Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Chemotaxis
  • Collagen / metabolism
  • Computer Simulation
  • Drug Combinations
  • Endocytosis
  • Humans
  • Laminin / metabolism
  • Matrix Metalloproteinases / metabolism
  • Membrane Proteins / metabolism*
  • Models, Biological*
  • Muscle Proteins / metabolism*
  • Neoplasm Invasiveness / pathology
  • Neoplasms / enzymology
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Proteoglycans / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Reproducibility of Results


  • Calcium-Binding Proteins
  • Drug Combinations
  • Laminin
  • MYOF protein, human
  • Membrane Proteins
  • Muscle Proteins
  • Proteoglycans
  • matrigel
  • Collagen
  • Receptor Protein-Tyrosine Kinases
  • Matrix Metalloproteinases