title: Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth.
abstract: Cells within the tumor microenvironment influence tumor growth through multiple mechanisms. Pericytes such as hepatic stellate cells are an important cell within the tumor microenvironment; their transformation into highly motile myofibroblasts leads to angiogenesis, stromal cell recruitment, matrix deposition, and ensuing tumor growth. Thus, a better understanding of mechanisms that regulate motility of pericytes is required. Focal adhesions (FAs) form a physical link between the extracellular environment and the actin cytoskeleton, a requisite step for cell motility. FAs contain a collection of proteins including the Ena/VASP family member, vasodilator-stimulated phosphoprotein (VASP); however, a role for VASP in FA development has been elusive. Using a comprehensive siRNA knockdown approach and a variety of VASP mutants coupled with complementary cell imaging methodologies, we demonstrate a requirement of VASP for optimal development of FAs and cell spreading in LX2 liver myofibroblasts, which express high levels of endogenous VASP. Rac1, a binding partner of VASP, acts in tandem with VASP to regulate FAs. In vivo, perturbation of Ena/VASP function in tumor myofibroblast precursor cells significantly reduces pericyte recruitment to tumor vasculature, myofibroblastic transformation, tumor angiogenesis, and tumor growth, providing in vivo pathobiologic relevance to these findings. Taken together, our results identify Ena/VASP as a significant modifier of tumor growth through regulation of FA dynamics and ensuing pericyte/myofibroblast function within the tumor microenvironment.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA. kang.ningling@mayo.edu
authors.forename: Ningling
authors.initials: N
authors.lastname: Kang
authors.forename: Usman
authors.initials: U
authors.lastname: Yaqoob
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Geng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bloch
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Liu
authors.forename: Timothy
authors.initials: T
authors.lastname: Gomez
authors.forename: Daniel
authors.initials: D
authors.lastname: Billadeau
authors.forename: Vijay
authors.initials: V
authors.lastname: Shah
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000637:transplantation; D022001:Focal Adhesions / Q000378:metabolism / Q000473:pathology*; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D059016:Tumor Microenvironment; D016596:Vinculin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000098662:Vasodilator-Stimulated Phosphoprotein; D016596:Vinculin; D020830:rac1 GTP-Binding Protein
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