Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer

Jérôme Levallet (1) , Tiphaine Biojout (1) , Céline Bazille (1, 2) , Manon Douyère (1) , Fatéméh Dubois (1, 2, 3) , Dimitri Leite Ferreira (1, 4) , Jasmine Taylor (1) , Sylvain Teulier (1, 4) , Jérôme Toutain (1) , Nicolas Elie (5) , Myriam Bernaudin (1) , Samuel Valable (1) , Emmanuel Bergot (1, 4) , Guénaëlle Levallet (2, 1, 3)

1 ISTCT - Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux
2 Département de Pathologie [CHU Caen]
3 SF-MOCAE
4 Service de pneumologie [CHU Caen]
5 CMABio3 - Centre de Microscopie Appliquée à la Biologie [Caen]

The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.

Domains: Life Sciences [q-bio]

Jérôme Levallet, Tiphaine Biojout, Céline Bazille, Manon Douyère, Fatéméh Dubois, et al.. Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer. Cell Death and Disease, 2023, 14, pp.823. ⟨10.1038/s41419-023-06345-3⟩. ⟨hal-04404933⟩