ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis.

Cinzia Martinengo,Domenico Ribatti,Qi Wang,Roberto Piva,Elisa Pellegrino,Roberto Chiarle,Fabio Pastorino,Cristina Mastini,Teresa Poggio,Claudia Voena,Maria Stella Scalzo,Mirco Ponzoni,Chiara Ambrogio,Ludovica Riera,Patrizia Perri,Matteo Menotti

doi:10.1158/0008-5472.can-14-0268

Abstract

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 with 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 (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1α and HIF2α 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, HIF2α, but not HIF1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1α and HIF2α. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK(+) tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.

Highlights

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in chromosomal rearrangements in anaplastic large-cell lymphoma (ALCL), non–small cell lung carcinoma (NSCLC; ref. 1), and other solid cancers [2]
echinoderm microtubule–associated protein-like 4 (EML4)–ALK mice showed significantly higher HIF2a transcripts than all the other lung cancer genotypes (Fig. 5F). Consistent with these data on HIFa regulation mediated by ALK in NSCLC, in genetically engineered mice (GEM) models VEGFA levels were significantly higher in EML4–ALK than in K-RasV12G, EGFRL858R, or B-RafV600E–mutated tumors (Supplementary Fig. S17B) and the inhibition of ALK decreased VEGFA expression in human NSCLC (Supplementary Fig. S17C), indicating a direct control of VEGFA by oncogenic ALK in NSCLC, as we showed in ALCL
Together with the evidences on the role of ALK in neuroblastoma tumor angiogenesis [12], collectively these data support the concept that controlling the hypoxia response could be one major function of oncogenic ALK in various tumor types

Summary

Introduction

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in chromosomal rearrangements in anaplastic large-cell lymphoma (ALCL), non–small cell lung carcinoma (NSCLC; ref. 1), and other solid cancers [2]. The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in chromosomal rearrangements in anaplastic large-cell lymphoma (ALCL), non–small cell lung carcinoma 1), and other solid cancers [2]. In ALCL the Nucleophosmin 1 (NPM1) gene and ALK generate the NPM–ALK fusion, but more than 20 other partners of. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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