HIF1α and HIF2α independently activate SRC to promote melanoma metastases

Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIP) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells. Using a Pten-deficient, Brarmutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1 alpha or HIF2 alpha abrogates metastasis without affecting primary tumor formation. HIF1 alpha and HIF2 alpha drive melanoma invasion and invadopodia formation through PDGFR alpha and focal adhesion kinase-mediated (FAK-mediated) activation of SRC and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1 alpha and HIF2 alpha activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.