ABSTRACT
Autophagy is a self-degradative mechanism involved in many biological processes, including cell death, survival, proliferation or migration. In tumors, autophagy plays an important role in tumorigenesis as well as cancer progression and resistance to therapies. Usually, a high level of autophagy in malignant cells has been associated with tumor progression and poor prognostic for patients. However, the investigation of autophagy levels in patients remains difficult, especially because quantification of autophagy proteins is challenging in the tumor microenvironment. In this study, we analyzed the expression of autophagy genes in non-small cell lung (NSCLC) cancer patients using public datasets and revealed an autophagy gene signature for proliferative and immune-checkpoint-expressed malignant cells in lung adenocarcinoma (LUAD). Analysis of autophagy-related gene expression profiles in tumor and adjacent tissues revealed differential signatures, namely signature A (23 genes) and signature B (12 genes). Signature B correlated with a bad prognosis and poor overall and disease-specific survival. Univariate and multivariate analyses revealed that this signature was an independent factor for prognosis. Moreover, patients with high expression of signature B exhibited more genes related to proliferation and fewer genes related to immune cells or immune response. The analysis of datasets from sorted fresh tumor cells or single cells revealed that signature B is predominantly represented in malignant cells, with poor expression in pan-immune population or in fibroblast or endothelial cells. Interestingly, autophagy was increased in malignant cells exhibiting high levels of signature B, which correlated with an elevated expression of genes involved in cell proliferation and immune checkpoint signaling. Taken together, our analysis reveals a novel autophagy-based signature to define the metabolic and immunogenic status of malignant cells in LUAD.
ABSTRACT
Autophagy is an important process for cellular homeostasis at critical steps of development or in response to environmental stress. In the context of cancers, autophagy has a significant impact on tumor occurrence and tumor cell growth. On the one hand, autophagy limits the transformation of precancerous cells into cancer cells at an early stage. However, on the other hand, it promotes cell survival, cell proliferation, metastasis and resistance to anti-tumor therapies in more advanced tumors. Autophagy can be induced by a variety of extracellular and intracellular stimulus. Viral infections have often been associated with a modulation of autophagy, with variable impacts on viral replication and on the survival of infected cells depending on the model studied. In a tumor context, the modulation of autophagy induced by the viral infection of tumor cells seems to have a significant impact on tumor progression. The aim of this review article is to present recent findings regarding the consequences of autophagy disturbance by viral infections on tumor behavior.
TITLE: L'autophagie modulée par les virus - Un rôle dans la progression tumorale. ABSTRACT: L'autophagie est un processus métabolique important pour maintenir l'homéostasie cellulaire à des moments critiques du développement et/ou en réponse à un stress environnemental. Cela est particulièrement pertinent dans le cas des cancers, pour lesquels il a été montré que l'autophagie a un impact important sur leur survenue et sur la croissance tumorale. D'une part, elle limite la transformation cancéreuse des cellules précancéreuses à un stade précoce, mais, d'autre part, elle favorise la survie et la prolifération cellulaires, les métastases et la résistance aux thérapies anti-tumorales dans les tumeurs plus avancées. L'autophagie peut être induite par une grande variété de stimulus extracellulaires et intracellulaires. Les infections virales ont souvent été associées à une modulation de l'autophagie, dont l'impact sur la réplication virale ou la survie des cellules infectées diffère selon le modèle étudié. Dans un contexte tumoral, certains mécanismes moléculaires complexes par lesquels la modulation de l'autophagie par les virus peut influencer le développement des cellules précancéreuses ou cancéreuses ont été révélés. Cette revue présente les découvertes récentes concernant les répercussions d'une perturbation de l'autophagie par l'infection virale sur la survenue et la progression des tumeurs cancéreuses.
Subject(s)
Neoplasms , Viruses , Autophagy , Humans , Neoplasms/therapy , Neoplastic Processes , Virus ReplicationABSTRACT
Autophagy is a self-degradative process important for balancing cellular homeostasis at critical times in development and/or in response to nutrient stress. This is particularly relevant in tumor model in which autophagy has been demonstrated to have an important impact on tumor behavior. In one hand, autophagy limits tumor transformation of precancerous cells in early stage, and in the other hand, it favors the survival, proliferation, metastasis, and resistance to antitumor therapies in more advanced tumors. This catabolic machinery can be induced by an important variety of extra- and intracellular stimuli. For instance, viral infection has often been associated to autophagic modulation, and the role of autophagy in virus replication differs according to the virus studied. In the context of tumor development, virus-modulated autophagy can have an important impact on tumor cells' fate. Extensive analyses have shed light on the molecular and/or functional complex mechanisms by which virus-modulated autophagy influences precancerous or tumor cell development. This review includes an overview of discoveries describing the repercussions of an autophagy perturbation during viral infections on tumor behavior.