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ABSTRACT
Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.
Abbreviations
| AIM1 | = | absent in melanoma 1 |
| AKT | = | AKT serine/threonine kinase |
| ATG3 | = | autophagy-related 3 |
| ATG4A | = | autophagy-related 4A cysteine peptidase |
| Atg8 | = | yeast autophagy-related 8 |
| ATG16L1 | = | autophagy-related 16 like 1 |
| BECN1 | = | Beclin 1 |
| BRAF | = | B-Raf proto-oncogene, serine/threonine kinase |
| BVES | = | blood vessel epicardial substance |
| CCLE | = | Cancer Cell Line Encyclopedia |
| FDR | = | false discovery rate |
| FISH | = | fluorescence in situ hybridization |
| GABARAPL1 | = | GABA type A receptor associated protein like 1 |
| GSEA | = | gene set enrichment analysis |
| MAP1LC3A | = | microtubule-associated protein 1 light chain 3 α |
| MAP1LC3B | = | microtubule- associated protein 1 light chain 3 β |
| MAP2K/MEK | = | mitogen-activated protein kinase kinase |
| MAPK | = | mitogen-activated protein kinase |
| MITF | = | melanogenesis associated transcription factor |
| PIK3CA | = | phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α |
| POPDC3 | = | popeye domain containing 3 |
| PRDM1 | = | PR domain 1 |
| PREP | = | prolyl endopeptidase |
| PTEN | = | phosphatase and tensin homolog |
| QRSL1 | = | glutaminyl-tRNA synthase (glutamine-hydrolyzing)-like 1 |
| RB1CC1 | = | RB1 inducible coiled-coil 1 |
| RTN4IP1 | = | reticulon 4 interacting protein 1 |
| RSEM | = | RNA-sequencing by expectation maximization |
| SEM | = | standard error of the mean |
| SHH | = | sonic hedgehog |
| SOX10 | = | SRY-box 10 |
| SQSTM1/p62 | = | sequestosome 1 |
| TCGA | = | the Cancer Genome Atlas |
| Tyr | = | tyrosinase |
| ULK1/2 | = | unc-51 like autophagy activating kinase 1/2 |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors thank all the colleagues in the CNIO Melanoma Group, in particular former member Alicia González-Serrano for their help and support; Sandra Barral (Columbia Univ, USA) for aid in statistical analyses; Juan Cruz Cigudosa (CNIO, Molecular Cytogenetics Unit) and Lydia Sanchez (CNIO, Histology and Immunohistochemistry Unit) for technical assistance with FISH and expression studies in tumor specimens, respectively. We also thank Jose A Esteban (CBMSO, Madrid) and Simón Méndez-Ferrer (CNIC) for critical reading of this manuscript, and Noburu Mizushima (Tokyo Medical and Dental University), Lionel Larue (Inst. Curie, France), and Martin McMahon (UCSF, USA) for Atg5flox/fox; Tyr:CreERT2, and BRAFCA mouse strains, respectively.
Funding
M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (projects SAF2011-28317, SAF2014-56868-R and RTC-2014-2442-1), as well as a Team Science Award by the Melanoma Research Alliance, and grants from the Worldwide Cancer Research and the Asociacion Española Contra el Cancer (AECC). M.G-F was funded by a Juan de la Cierva postdoctoral fellowship from the Spanish Ministry of Education and P.K and M.C. by predoctoral fellowships from Fundación La Caixa.
