Blocking the Angiopoietin-2-dependent Integrin beta-1 signaling axis abrogates small cell lung cancer invasion and metastasis

Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. 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 primary and metastatic SCLC patient samples 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/Integrin beta-1-dependent pathway in tumor cells, mediated by focal adhesion kinase-Src kinase signaling. Strikingly, CRISPR-Cas9 knock out of Integrin beta-1 or blocking Integrin beta-1 signaling by an anti-Angiopoietin-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched primary and metastatic SCLC patient samples confirmed a strong increase of Integrin beta-1 in liver metastasis in comparison to the primary tumor. We further show that Angiopoietin-2 blockade combined with anti-VEGFR and PD-1-targeted treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of Angiopoietin-2/Integrin beta-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a new effective treatment strategy for patients with SCLC.