The gluttonous side of malignant melanoma: basic and clinical implications of macroautophagy

Chęcińska, Agnieszka; Soengas, Marı́a S.

doi:10.1111/j.1755-148x.2011.00927.x

Cited by 24 publications

(26 citation statements)

References 123 publications

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“…A better knowledge of genetic and pharmacological modulators of autophagy would have important basic and clinical implications for cutaneous melanoma. Histological studies revealed a great intra and inter-tumoral variability in multiple autophagy genes (5). One of the most intriguing changes in expression relates to the autophagy factor, autophagy related gene 5 (ATG5), a key player in autophagosome formation.…”

Section: Introductionmentioning

confidence: 99%

ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

et al. 2017

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Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiological relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account.

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Section: Introductionmentioning

confidence: 99%

ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

et al. 2017

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“…While immunochemistry of normal human melanocytes revealed low expression of LC3 protein, a histological MA marker, focal staining of LC3 molecules increased in spreading subcutaneous melanoma consistent with increased tumor MA (Checinska and Soengas, 2011; Corazzari et al, 2013). Immunohistochemical analysis of early and late stage melanomas revealed that late stage tumors associated with poor prognosis, expressed reduced levels of p62, a protein whose turnover is linked to enhanced MA (Ellis et al, 2014).…”

Section: Discussionmentioning

confidence: 95%

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

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Sinn

Sandusky

et al. 2018

Front. Cell Dev. Biol.

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Autophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth in vitro and in vivo. Solid tumors such as melanomas encounter a variety of stresses in vivo including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread. Here, we report that in response to the anti-tumor, pro-inflammatory cytokine interferon-gamma, melanoma cell expression of LAMP2C mRNA significantly increased. These results prompted an investigation of whether increased melanoma cell expression of LAMP-2C might represent a mechanism to control or limit human melanoma growth and survival. In this study, enhanced expression of human LAMP-2C in melanoma cells perturbed macroautophagy and chaperone-mediated autophagy in several human melanoma lines. In vitro analysis showed increasing LAMP-2C expression in a melanoma cell line, triggered reduced cellular LAMP-2A and LAMP-2B protein expression. Melanoma cells with enhanced LAMP-2C expression displayed increased cell cycle arrest, increased expression of the cell cycle regulators Chk1 and p21, and greater apoptosis and necrosis in several cell lines tested. The increased abundance of Chk1 protein in melanoma cells with increased LAMP-2C expression was not due to higher CHEK1 mRNA levels, but rather an increase in Chk1 protein abundance including Chk1 molecules phosphorylated at Ser345. Human melanoma cell xenografts with increased LAMP-2C expression, displayed reduced growth in immune compromised murine hosts. Melanomas with high LAMP-2C expression showed increased necrosis and reduced cell density upon histological analysis. These results reveal a novel role for LAMP-2C in negatively regulating melanoma growth and survival.

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“…11,27 The specific contribution of other lysosomal-associated processes such as (macro)autophagy to melanoma initiation, progression and response to therapy is still under evaluation. 28,29 Melanomas are long known for their ability to induce autophagosome formation in response to a variety of endogenous stressinducing factors (e.g., deregulated BRAF>MAPK oncogenic signals) [30][31][32] and external cues (including hypoxia, nutrient deprivation, and a broad spectrum of therapeutic agents, among many others). 29,33,34 However, lysosomal-dependent degradation may favor or inhibit cell survival, depending on the identity and/or duration of the stimuli.…”

Section: Introductionmentioning

confidence: 99%

“…29,33,34 However, lysosomal-dependent degradation may favor or inhibit cell survival, depending on the identity and/or duration of the stimuli. 28,29 Mechanisms underlying these dual functions remain unclear. Multitumor genomic or transcriptomic profiles have not been performed to determine whether melanomas can regulate or target autophagy factors in a lineage-specific manner.…”

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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The gluttonous side of malignant melanoma: basic and clinical implications of macroautophagy

Cited by 24 publications

References 123 publications

ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

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

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