Identification of secreted proteins that reflect autophagy dynamics within tumor cells

Kraya, Adam; Piao, Shengfu; Xu, Xiaowei; Zhang, Gao; Herlyn, Meenhard; Gimotty, Phyllis A.; Levine, Beth; Amaravadi, Ravi K.; Speicher, David W.

doi:10.4161/15548627.2014.984273

Cited by 101 publications

(105 citation statements)

References 60 publications

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“…Autophagy-dependent secretion of the proinvasive cytokine IL6 is one of the critical factors for invasion (Lock et al 2014). Measurement of circulating cytokines secreted by tumor cells in an autophagy-dependent manner could be useful to gauge autophagy levels within patient tumors (Kraya et al 2015). These studies support the idea that autophagy promotes the coordinate secretion of cytokines favoring tumor cell invasion and broach the hypothesis that autophagy may direct non-cell-autonomous functions in tumor cells as well as associated stromal constituents by impacting secretory capacity.…”

Section: New Roles For Autophagy Identified In Cancer Progressionmentioning

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: New Roles For Autophagy Identified In Cancer Progressionmentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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“…Recently, the secretion of IL-1β has been linked to the autophagy machinery [1, 3, 14]. These studies have been extended and expanded by several groups [19, 20, 25, 26]. This was made possible in part by the details of autophagy-assisted unconventional secretion uncovered in yeast through the power of genetics [12, 13].…”

Section: Secretory Autophagy As a Form Of Unconventional Protein Secrmentioning

confidence: 99%

“…In contrast to degradative autophagy, it has become slowly but increasingly apparent that autophagy has other, sometimes biogenesis-associated functions as well as a role in unconventional secretion (secretory autophagy; Figure 2). Secretory autophagy exports a range of cytoplasmic substrates (Table 1) [2, 12–19] [20, 21]. This review primarily examines the developing concept of secretory autophagy including its cargo, biological functions, and the currently limited understanding of its regulation.…”

Section: Introductionmentioning

confidence: 99%

Secretory autophagy

Ponpuak

Mandell

Kimura

et al. 2015

Current Opinion in Cell Biology

421

356

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Autophagy, once viewed exclusively as a cytoplasmic auto-digestive process, has its less intuitive but biologically distinct non-degradative roles. One manifestation of these functions of the autophagic machinery is the process termed secretory autophagy. Secretory autophagy facilitates unconventional secretion of the cytosolic cargo such as leaderless cytosolic proteins, which unlike proteins endowed with the leader (N-terminal signal) peptides cannot enter the conventional secretory pathway normally operating via the endoplasmic reticulum and the Golgi apparatus. Secretory autophagy may also export more complex cytoplasmic cargo and help excrete particulate substrates. Autophagic machinery and autophagy as a process also affect conventional secretory pathways, including the constitutive and regulated secretion, as well as promote alternative routes for trafficking of integral membrane proteins to the plasma membrane. Thus, autophagy and autophagic factors are intimately intertwined at many levels with secretion and polarized sorting in eukaryotic cells.

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“…Nevertheless, comparative analyses of Atg5/ATG5 and Atg7/ATG7, in mouse models and human specimens, are granted as they may prove relevant to identify differential regulators and functional targets of these genes, for example, in the modulation of the tumor secretome. 75 In this context, an attractive possibility is that the partial downregulation of ATG5 (but not ATG7) in melanomas reflects a developmental program shared by the lineage-specific drivers MITF 11,27 and RAB7 24,25 which act in part by providing a fine tuning to lysosomal-associated secretory programmes. 26 Together, our results identified ATG5 heterozygous loss as a distinctive feature of aggressive melanomas, selectively exploiting cytogenetic alterations at the chromosome 6q21 band, and contributing to disease-free survival in a manner not shared by other tumor types.…”

Section: Discussionmentioning

confidence: 99%

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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Identification of secreted proteins that reflect autophagy dynamics within tumor cells

Cited by 101 publications

References 60 publications

Recent insights into the function of autophagy in cancer

Recent insights into the function of autophagy in cancer

Secretory autophagy

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

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