biostudies-literatureMeder LGerman Research FoundationGerman federal state North Rhine WestphaliaCenter for Molecular Medicine Cologne FundsFritz-Thyssen FoundationBoehringer IngelheimGerman Cancer AidElse Kröner-Fresenius Foundatione166402https://www.ebi.ac.uk/biostudies/studies/S-EPMC11141935biostudies-literatureUnknown9(10)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 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 β-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin β-1 or blocking Integrin β-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in JCI insightBlocking the angiopoietin-2-dependent integrin β-1 signaling axis abrogates small cell lung cancer invasion and metastasis.PMC11141935LMMemorial Grant 2018_EKMS.35RTU70113307EKFS-2014-A06Fritz-Thyssen FoundationUL379/1-11411ng00570113009SFB-1399/A01/C02LS-1-1-030a111724Compes ABlazquez ROrschel CIUllrich RTOdenthal MButtner REich MLMeder LErcanoglu MSKlein FKoker MDietlein FHallek MHilberg FOtto CJReinhardt HCBragelmann JDahling SFlorin ANill MSelenz CBorchmann SfalseBlocking the angiopoietin-2-dependent integrin β-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 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 β-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin β-1 or blocking Integrin β-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in 2024-01-01T00:00:00Z2024 May2026-07-15T07:52:20.43Z2026-07-01T03:07:55.178ZS-EPMC111419353877515310.1172/jci.insight.166402