Cross-cancer profiling of molecular alterations within the human autophagy interaction network

Lebovitz, Chandra B.; Robertson, A. Gordon; Goya, Rodrigo; Jones, Steven J.M.; Morin, Ryan D.; Marra, Marco A.; Gorski, Sharon M.

doi:10.1080/15548627.2015.1067362

Cited by 109 publications

(101 citation statements)

References 92 publications

(83 reference statements)

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“…The core autophagy machinery is generally not targeted by high-frequency somatic singlenucleotide mutations across cancers in TCGA (Lebovitz et al 2015). Although a small number of recurrent mutations in RB1CC1/FIP200, ULK4, and ATG7 are found, these are rare and limited to few tumor types.…”

Section: Core Autophagy Genes Are Generally Not Mutated In Cancermentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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Section: Core Autophagy Genes Are Generally Not Mutated In Cancermentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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“…We were particularly interested in the core machinery for autophagosome formation because, not being frequently targeted in various carcinomas, 35 it could represent a potential distinctive feature in melanoma, inasmuch as other lysosomal functions related to vesicular trafficking. 24 To this end, we selected wellknown orthologs of the LC3/Atg8 protein (GABARAPL1 and MAP1LC3A), and a series of additional key modulators of phagophore initiation and maturation (ATG3, ATG4A, ATG5, ATG7, ATG10, ATG12, ATG16L1, BECN1, RB1CC1, ULK1 and ULK2).…”

Section: Resultsmentioning

confidence: 99%

“…46,69 Dissecting the impact of autophagy in cancer has the added complication of rather unconserved expression patterns, as recently demonstrated in glioblastomas and 11 different carcinoma types by cross-cancer profiling of molecular alterations. 35 Here we extended this heterogeneity to melanomas and a broad spectrum of tumors of various etiologies, emphasizing the need for functional validation in physiologically relevant systems. Indeed, without the inducible mouse models generated in this study, an unsupervised computational analysis may have missed the relevance of ATG5 heterozygosity in melanoma progression and response to targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, it is unclear whether melanomas spare the core autophagy machinery from mutation, targeting instead other genes (for example, regulators of the autophagy network) as recently reported for glioblastomas and multiple carcinoma types. 35 Indeed, the expression and function of factors involved in autophagosome assembly is inconsistent across the melanoma literature. 28,29 Thus, autophagy genes such as MAP1LC3 or BECN1 may be up-or downregulated depending on the study.…”

Section: Introductionmentioning

confidence: 99%

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Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss ofATG5

et al. 2016

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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.

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“…Iman Meziane, 1 10 Anna Jauch, 11 Gareth J. Morgan, 3 Richard Houlston, 9,10 Hartmut Goldschmidt, 2,12 Paolo Milani, 13,14 Giampaolo Merlini, 13,14 …”

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confidence: 99%