Vasodilator-Stimulated Phosphoprotein Promotes Activation of Hepatic Stellate Cells by Regulating Rab11-Dependent Plasma Membrane Targeting of Transforming Growth Factor Beta Receptors

Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-) 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--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 (-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF--mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF- receptor II (TRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TRII to the plasma membrane, thereby desensitizing HSCs to TGF-1 stimulation. Conclusions: Our study demonstrates a requirement of VASP for TGF--mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TRII 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. (Hepatology 2015;61:361-374)