The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma

• DOI: 10.1038/s41416-018-0128-4
• Publication Date: 2018-05-22T15:15:27Z
• Authors: Cherine Abou Faycal; Elisabeth Brambilla; Jackeline Agorreta; Nina Lepeltier; Thibault Jacquet; Nicolas Lemaître; Anouk Emadali; Anthony Lucas; Pedro M Lacal; Luis Montuenga; Ruben Pio; Sylvie Gazzeri; Beatrice Eymin
• Keywords: 0301 basic medicine; 570; Lung Neoplasms; RNA splicing; [SDV]Life Sciences [q-bio]; 610; Angiogenesis Inhibitors; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Article; Anti-angiogenic therapies; Mice; 03 medical and health sciences; VEGF-A/VEGFR; β1 integrin; Squamous cell lung carcinoma (SQLC); Carcinoma, Non-Small-Cell Lung; Tumor Cells, Cultured; Animals; Humans; Protein Isoforms; sVEGFR1; [SDV.BC] Life Sciences [q-bio]/Cellular Biology; Vascular Endothelial Growth Factor Receptor-1; Integrin beta1; Lung Cancer; Receptor Cross-Talk; Xenograft Model Antitumor Assays; 3. Good health; [SDV] Life Sciences [q-bio]; Autocrine Communication; Carcinoma, Squamous Cell; Disease Progression

While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.