title: Palladin mediates stiffness-induced fibroblast activation in the tumor microenvironment.
abstract: Mechanical properties of the tumor microenvironment have emerged as key factors in tumor progression. It has been proposed that increased tissue stiffness can transform stromal fibroblasts into carcinoma-associated fibroblasts. However, it is unclear whether the three to five times increase in stiffness seen in tumor-adjacent stroma is sufficient for fibroblast activation. In this study we developed a three-dimensional (3D) hydrogel model with precisely tunable stiffness and show that a physiologically relevant increase in stiffness is sufficient to lead to fibroblast activation. We found that soluble factors including CC-motif chemokine ligand (CCL) chemokines and fibronectin are necessary for this activation, and the combination of C-C chemokine receptor type 4 (CCR4) chemokine receptors and β1 and β3 integrins are necessary to transduce these chemomechanical signals. We then show that these chemomechanical signals lead to the gene expression changes associated with fibroblast activation via a network of intracellular signaling pathways that include focal adhesion kinase (FAK) and phosphoinositide 3-kinase (PI3K). Finally, we identify the actin-associated protein palladin as a key node in these signaling pathways that result in fibroblast activation.
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: McLane
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, New York. Electronic address: ligonl@rpi.edu.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Ligon
mesh_terms: D018829:Adhesins, Bacterial; D002460:Cell Line; D019742:Chemokines, CC / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004548:Elasticity; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D020100:Hydrogels; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D054398:Receptors, CCR4 / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*
chemical_list: D018829:Adhesins, Bacterial; D019742:Chemokines, CC; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020100:Hydrogels; D019012:Integrin beta1; D039661:Integrin beta3; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054398:Receptors, CCR4; C515354:CCR4 protein, human; C412722:PALLD protein, human; C048165:adhesin, Staphylococcus aureus