title: Vasodilator-stimulated phosphoprotein promotes activation of hepatic stellate cells by regulating Rab11-dependent plasma membrane targeting of transforming growth factor beta receptors.
abstract: Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-β) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-β-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF-β1 stimulation.
  
  
  CONCLUSIONS
  Our study demonstrates a requirement of VASP for TGF-β-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver.
authors.affiliation: GI Research Unit and Cancer Cell Biology Program, Mayo Clinic, Rochester, MN; Department of Hepatobillary Surgery, the 1st Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Kangsheng
authors.initials: K
authors.lastname: Tu
authors.forename: Jiachu
authors.initials: J
authors.lastname: Li
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Verma
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Liu
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.forename: Georg
authors.initials: G
authors.lastname: Lamprecht
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xiang
authors.forename: Luyang
authors.initials: L
authors.lastname: Guo
authors.forename: Renumathy
authors.initials: R
authors.lastname: Dhanasekaran
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
authors.forename: Ningling
authors.initials: N
authors.lastname: Kang
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D058628:Myofibroblasts / Q000473:pathology; D019899:Paracrine Communication; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein; D000099193:rab11 GTP-Binding Proteins
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D020691:rab GTP-Binding Proteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D000099193:rab11 GTP-Binding Proteins