title: HIF1α and HIF2α independently activate SRC to promote melanoma metastases.
abstract: 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 HIF1α or HIF2α abrogates metastasis without affecting primary tumor formation. HIF1α and HIF2α drive melanoma invasion and invadopodia formation through PDGFRα 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 HIF1α and HIF2α activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Hanna
authors.forename: Bhavani
authors.initials: B
authors.lastname: Krishnan
authors.forename: Sean T
authors.initials: ST
authors.lastname: Bailey
authors.forename: Stergios J
authors.initials: SJ
authors.lastname: Moschos
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Kuan
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Lukas D
authors.initials: LD
authors.lastname: Osborne
authors.forename: Marni B
authors.initials: MB
authors.lastname: Siegel
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: E Tim
authors.initials: ET
authors.lastname: O'Brien
authors.forename: Richard
authors.initials: R
authors.lastname: Superfine
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009362:Neoplasm Metastasis; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051059:PTEN Phosphohydrolase; D048493:Proto-Oncogene Proteins B-raf; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1; C482119:BRAF protein, human; C494929:PTEN protein, human
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