| First Author | Hanna SC | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 5 | Pages | 2078-93 |
| PubMed ID | 23563312 | Mgi Jnum | J:201460 |
| Mgi Id | MGI:5514128 | Doi | 10.1172/JCI66715 |
| Citation | Hanna SC, et al. (2013) HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases. J Clin Invest 123(5):2078-93 |
| abstractText | Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) 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, Braf-mutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1alpha or HIF2alpha abrogates metastasis without affecting primary tumor formation. HIF1alpha and HIF2alpha drive melanoma invasion and invadopodia formation through PDGFRalpha 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 HIF1alpha and HIF2alpha activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling. |
