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Blocking the angiopoietin-2-dependent integrin β-1 signaling axis abrogates small cell lung cancer invasion and metastasis

Meder L, Orschel CI, Otto CJ, Koker M, Brägelmann J, Ercanoglu MS, Dähling S, Compes A, Selenz C, Nill M, Dietlein F, Florin A, Eich ML, Borchmann S, Odenthal M, Blazquez R, Hilberg F, Klein F, Hallek M, Büttner R, Reinhardt HC, Ullrich RT (2024)

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Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 9

Article Number: e166402

Journal Issue: 10

DOI: 10.1172/jci.insight.166402

Abstract

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 vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin β-1 in liver metastasis in comparison with the primary tumor. We further show that ANG-2 blockade combined with PD-1-targeted by anti-PD-1 treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of ANG-2/Integrin β-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a potentially new effective treatment strategy for patients with SCLC.

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How to cite

APA:

Meder, L., Orschel, C.I., Otto, C.J., Koker, M., Brägelmann, J., Ercanoglu, M.S.,... Ullrich, R.T. (2024). Blocking the angiopoietin-2-dependent integrin β-1 signaling axis abrogates small cell lung cancer invasion and metastasis. JCI Insight, 9(10). https://doi.org/10.1172/jci.insight.166402

MLA:

Meder, Lydia, et al. "Blocking the angiopoietin-2-dependent integrin β-1 signaling axis abrogates small cell lung cancer invasion and metastasis." JCI Insight 9.10 (2024).

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