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Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched samples from patients with primary and metastatic SCLC to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2 (ANG-2)\/Integrin \u03b2-1\u2013dependent pathway in tumor cells, mediated by focal adhesion kinase\/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin \u03b2-1 or blocking Integrin \u03b2-1 signaling by an anti\u2013ANG-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin \u03b2-1 in liver metastasis in comparison with the primary tumor. 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