Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth

Ningling Kang, Usman Yaqoob, Zhimin Geng, Kenneth Bloch, Chunsheng Liu, Timothy Gomez, Daniel D Billadeau, Vijay Shah

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1888-1900
Number of pages13
JournalAmerican Journal of Pathology
Volume177
Issue number4
DOIs
StatePublished - Oct 2010

Fingerprint

Focal Adhesions
Tumor Microenvironment
Myofibroblasts
Growth
Pericytes
Neoplasms
vasodilator-stimulated phosphoprotein
Hepatic Stellate Cells
Stromal Cells
Actin Cytoskeleton
Small Interfering RNA
Cell Movement

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth. / Kang, Ningling; Yaqoob, Usman; Geng, Zhimin; Bloch, Kenneth; Liu, Chunsheng; Gomez, Timothy; Billadeau, Daniel D; Shah, Vijay.

In: American Journal of Pathology, Vol. 177, No. 4, 10.2010, p. 1888-1900.

Research output: Contribution to journalArticle

Kang, Ningling ; Yaqoob, Usman ; Geng, Zhimin ; Bloch, Kenneth ; Liu, Chunsheng ; Gomez, Timothy ; Billadeau, Daniel D ; Shah, Vijay. / Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth. In: American Journal of Pathology. 2010 ; Vol. 177, No. 4. pp. 1888-1900.
@article{4b3bcb0c41d943adbe8970e959ebeaaa,
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.",
author = "Ningling Kang and Usman Yaqoob and Zhimin Geng and Kenneth Bloch and Chunsheng Liu and Timothy Gomez and Billadeau, {Daniel D} and Vijay Shah",
year = "2010",
month = "10",
doi = "10.2353/ajpath.2010.100187",
language = "English (US)",
volume = "177",
pages = "1888--1900",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth

AU - Kang, Ningling

AU - Yaqoob, Usman

AU - Geng, Zhimin

AU - Bloch, Kenneth

AU - Liu, Chunsheng

AU - Gomez, Timothy

AU - Billadeau, Daniel D

AU - Shah, Vijay

PY - 2010/10

Y1 - 2010/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957356733&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957356733&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2010.100187

DO - 10.2353/ajpath.2010.100187

M3 - Article

VL - 177

SP - 1888

EP - 1900

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -