ALK-dependent control of hypoxia inducible factors mediates tumor growth and metastasis
Menée in vitro et in vivo sur des modèles de lymphome anaplasique à grandes cellules et de carcinome du poumon non à petites cellules présentant des réarrangements du gène ALK, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de certains facteurs induits par l'hypoxie, ALK favorise la croissance tumorale et le processus métastatique
Rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene are defining events in several tumors, including Anaplastic Large Cell Lymphoma (ALCL) and Non-Small Cell Lung Carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared to other types of T cell lymphoma or EGFR and K-RAS mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC we found that under hypoxic conditions ALK directly regulated the abundance of Hypoxia-Inducible Factors (HIFs), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF-1α and HIF-2α in hypoxic conditions required ALK activity and its downstream signaling proteins Stat3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF-2α, but not HIF-1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF-1α and HIF-2α. In conclusion, we uncovered an ALK specific regulation of the hypoxia response across different ALK positive tumor types, and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.