title: Sensing and modulation of invadopodia across a wide range of rigidities.
abstract: Recent studies have suggested that extracellular matrix rigidity regulates cancer invasiveness, including the formation of cellular invadopodial protrusions; however, the relevant mechanical range is unclear. Here, we used a combined analysis of tissue-derived model basement membrane (BM) and stromal matrices and synthetic materials to understand how substrate rigidity regulates invadopodia. Urinary bladder matrix-BM (UBM-BM) was found to be a rigid material with elastic moduli of 3-8 MPa, as measured by atomic force microscopy and low-strain tensile testing. Stromal elastic moduli were ∼6-fold lower, indicating a more compliant material. Using synthetic substrates that span kPa-GPa moduli, we found a peak of invadopodia-associated extracellular matrix degradation centered around 30 kPa, which also corresponded to a peak in invadopodia/cell. Surprisingly, we observed another peak in invadopodia numbers at 2 GPa as well as gene expression changes that indicate cellular sensing of very high moduli. Based on the measured elastic moduli of model stroma and BM, we expected to find more invadopodia formation on the stroma, and this was verified on the stromal versus BM side of UBM-BM. These data suggest that cells can sense a wide range of rigidities, up into the GPa range. Furthermore, there is an optimal rigidity range for invadopodia activity that may be limited by BM rigidity.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennesee.
authors.forename: Aron
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Nazanin S
authors.initials: NS
authors.lastname: Ruppender
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennesee.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Branch
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: M K
authors.initials: MK
authors.lastname: Sewell-Loftin
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Boyer
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Candiello
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: W David
authors.initials: WD
authors.lastname: Merryman
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Guelcher
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennesee; Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennesee. Electronic address: alissa.weaver@vanderbilt.edu.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
mesh_terms: D000180:Acrylic Resins / Q000494:pharmacology; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects / Q000378:metabolism*; D055119:Elastic Modulus / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D011140:Polyurethanes / Q000494:pharmacology; D011312:Pressure; D034421:Sus scrofa; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D000099166:Polyacrylamides
chemical_list: D000180:Acrylic Resins; D011140:Polyurethanes; D000099166:Polyacrylamides