HIF1α and HIF2α independently activate SRC to promote melanoma invasion and metastasis

HIF1α and HIF2α independently activate SRC to promote melanoma invasion and metastasis Public Deposited

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Creator

Hanna, Sara
- Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology

Abstract

Melanoma incidence is increasing at an epidemic rate of 3% per year. When caught early, the disease is easily curable with surgical removal of the primary tumor. However, melanoma is notable for its propensity to metastasize, the leading cause of death in cancer patients. Here we study the role of the hypoxia-inducible factors in the malignant progression of melanoma, both in vivo in a genetically engineered mouse model of metastatic melanoma, and in vitro, in human melanoma cell lines. The hypoxia-inducible factor (HIF) family of transcription factors are upregulated in melanoma by key oncogenic drivers and transactivate genes involved in cancer initiation, progression, and metastases. We show that either Hif1α or Hif2α inactivation abrogates metastasis in a Pten- deficient, Braf-mutant genetically engineered mouse model of melanoma without affecting primary tumor formation. HIF1α and HIF2α drive melanoma invasion and invadopodia formation and mediate these effects by activation of SRC, through PDGFRα and FAK respectively, and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1α and HIF2α activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.

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