Abstract
Extracellular matrix (ECM)-induced β1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the β1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM–mediated β1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)–mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the β1-integrin-FAK signaling. Additionally, VASP regulates the β1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated β1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, β1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.
Highlights
Integrins are transmembrane receptors for extracellular matrix (ECM) components such as fibronectin, vitronectin, and collagen
vasodilator-stimulated phosphoprotein (VASP) plays a role in cell proliferation and migration through regulating actin dynamics, this study focused on the role of VASP in ECMmediated adhesion and survival signals because the initial ECMmediated signals in cancer cells disseminated into the liver are a key for liver metastasis development
Our data, revealing that VASP is upregulated in the majority of colorectal cancers (CRCs) and PDACs with its levels correlated with liver metastasis and reduced patient survival, support an idea that assays against this protein may be developed to serve as a prognostic marker for CRCs and PDACs
Summary
Integrins are transmembrane receptors for extracellular matrix (ECM) components such as fibronectin, vitronectin, and collagen. YAP1/TAZ are transcriptional coactivators that promote TEAD/TEF dependent gene transcription and their functions are regulated by RhoA or F-actin.20,22,23 These observations led us to test if YAP1/TAZ represent as a missing link between the β1-integrin-FAK signaling. We analyzed IHC data of 27 patients with paired model and two experimental liver metastasis mouse models, we primary CRCs and liver biopsies and found that in CRCs expressing demonstrated that VASP was required for the ECM–mediated β1- high levels of VASP (++ to +++), 14 out of 18 cases (77.8%) had integrin-FAK-YAP1/TAZ signaling and GI cancer liver metastasis CRC metastases in the liver (Fig. 1c). Ing β1-integrin activation and [2] inducing YAP1/TAZ depho- VASP is upregulated in the majority of CRCs with its levels sphorylation to enhance their protein stability in cells.
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