Extracellular matrix rigidity promotes invadopodia activity.
Invadopodia are actin-rich subcellular protrusions with associated proteases used by cancer cells to degrade extracellular matrix (ECM) [1]. Molecular components of invadopodia include branched actin-assembly proteins, membrane trafficking proteins, signaling proteins, and transmembrane proteinases [1]. Similar structures exist in nontransformed cells, such as osteoclasts and dendritic cells, but are generally called podosomes and are thought to be more involved in cell-matrix adhesion than invadopodia [2-4]. Despite intimate contact with their ECM substrates, it is unknown whether physical or chemical ECM signals regulate invadopodia function. Here, we report that ECM rigidity directly increases both the number and activity of invadopodia. Transduction of ECM-rigidity signals depends on the cellular contractile apparatus [5-7], given that inhibition of nonmuscle myosin II, myosin light chain kinase, and Rho kinase all abrogate invadopodia-associated ECM degradation. Whereas myosin IIA, IIB, and phosphorylated myosin light chain do not localize to invadopodia puncta, active phosphorylated forms of the mechanosensing proteins p130Cas (Cas) and focal adhesion kinase (FAK) are present in actively degrading invadopodia, and the levels of phospho-Cas and phospho-FAK in invadopodia are sensitive to myosin inhibitors. Overexpression of Cas or FAK further enhances invadopodia activity in cells plated on rigid polyacrylamide substrates. Thus, in invasive cells, ECM-rigidity signals lead to increased matrix-degrading activity at invadopodia, via a myosin II-FAK/Cas pathway. These data suggest a potential mechanism, via invadopodia, for the reported correlation of tissue density with cancer aggressiveness.
Alexander
Nelson R
NR
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Branch
Kevin M
KM
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Parekh
Aron
A
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Clark
Emily S
ES
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Iwueke
Izuchukwu C
IC
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.
Guelcher
Scott A
SA
Department of Chemical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
Weaver
Alissa M
AM
Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.|Department of Pathology, Vanderbilt University, Nashville, TN 37232, USA.
D008841:Actin Cytoskeleton / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions / Q000502:physiology* / Q000648:ultrastructure; D050719:Crk-Associated Substrate Protein / Q000032:analysis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology* / Q000648:ultrastructure; D051417:Focal Adhesion Kinase 1 / Q000032:analysis / Q000502:physiology; D005780:Gelatin / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D024462:Myosin Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D009281:Naphthalenes / Q000494:pharmacology; D015398:Signal Transduction
D001381:Azepines; C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D016023:Integrins; D009281:Naphthalenes; C070571:ML 7; C472645:blebbistatin; D005780:Gelatin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D009219:Myosin-Light-Chain Kinase; D024462:Myosin Type II