title: ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis.
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.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Martinengo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Poggio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Menotti
authors.affiliation: Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Scalzo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mastini
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pellegrino
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Riera
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Piva
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy. National Cancer Institute "Giovanni Paolo II," Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pastorino
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perri
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy. claudia.voena@unito.it roberto.chiarle@childrens.harvard.edu.
authors.forename: Claudia
authors.initials: C
authors.lastname: Voena
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Experimental Research and Medical Studies (CERMS), Torino, Italy. Department of Pathology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts. claudia.voena@unito.it roberto.chiarle@childrens.harvard.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C117307:KRAS protein, human; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C512478:EGFR protein, human