Leonardi Lucas, Siberil Sophie, Alifano Marco, Cremer Isabelle, Joubert Pierre-Emmanuel
Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, 75006 Paris, France.
Faculté des Sciences, Sorbonne Université, 75005 Paris, France.
Cancers (Basel). 2022 Jul 16;14(14):3462. doi: 10.3390/cancers14143462.
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.
自噬是一种自我降解机制，参与许多生物学过程，包括细胞死亡、存活、增殖或迁移。在肿瘤中，自噬在肿瘤发生、癌症进展以及对治疗的抵抗中发挥重要作用。通常，恶性细胞中高水平的自噬与肿瘤进展及患者预后不良相关。然而，对患者自噬水平的研究仍然困难，特别是因为在肿瘤微环境中自噬蛋白的定量具有挑战性。在本研究中，我们使用公开数据集分析了非小细胞肺癌（NSCLC）患者中自噬基因的表达，并揭示了肺腺癌（LUAD）中增殖性和免疫检查点表达的恶性细胞的自噬基因特征。对肿瘤组织和相邻组织中自噬相关基因表达谱的分析揭示了不同的特征，即特征A（23个基因）和特征B（12个基因）。特征B与不良预后以及总体和疾病特异性生存率低相关。单因素和多因素分析表明，该特征是预后的独立因素。此外，特征B高表达的患者表现出更多与增殖相关的基因，而与免疫细胞或免疫反应相关的基因较少。对分选的新鲜肿瘤细胞或单细胞数据集的分析表明，特征B主要在恶性细胞中表现，在全免疫群体、成纤维细胞或内皮细胞中表达较低。有趣的是，在表现出高水平特征B的恶性细胞中自噬增加，这与参与细胞增殖和免疫检查点信号传导的基因表达升高相关。综上所述，我们的分析揭示了一种基于自噬的新特征，以定义LUAD中恶性细胞的代谢和免疫原性状态。
