■自噬在癌症进展和治疗抵抗中起重要作用,自噬是肿瘤发病机制的基础,化疗耐药的进一步机制仍然未知。
■在这项研究中,通过单样本基因集富集分析(ssGSEA)方法,鉴定了一个自噬45基因列表来评估样品的自噬活性,通过六个GEO数据集验证了自噬表型。它被进一步用于将肿瘤区分为自噬评分高和评分低的亚型。分析它们的转录组景观,包括生存分析,自噬和抗性相关基因的相关性分析,生物功能富集,以及免疫和缺氧相关和基因组异质性比较,在TCGA泛癌症数据集中。此外,我们结合多个GEO数据集和体外实验对乳腺癌化疗耐药中的自噬状态进行了分析,以验证潜在的抗癌药物逆转化疗耐药的机制,包括CCK-8细胞活力测定,RT-qPCR,和免疫荧光。
■45基因列表用于鉴定自噬得分高和得分低的亚型,并进一步分析其多维特征。我们证明,癌症自噬状态与显著不同的预后相关,分子改变,生物过程激活,免疫细胞浸润,缺氧状态,和特定的突变过程。自噬评分低的亚型与评分高的亚型相比,显示出更有利的预后。与它们的免疫激活特征有关,表现为高免疫细胞浸润,包括高CD8+T,Tfh,Treg,NK细胞,和肿瘤相关巨噬细胞M1/M2。自噬评分低亚型也表现出高缺氧评分,在不同的自噬状态下,缺氧肿瘤的预后差异显着。因此,自噬引发的“双刃”细胞命运可能与免疫微环境和缺氧诱导密切相关。结果表明,自噬失调与许多癌症及其治疗抗性有关,并且自噬是由抗性逆转的药物反应诱导的。在五个乳腺癌GEO数据集中,并通过体外实验进行了验证。体外,双氢青蒿素和青蒿琥酯可以逆转乳腺癌多柔比星耐药,通过上调LC3B和ATG7诱导自噬。
■我们的研究为自噬相关的分子和肿瘤微环境模式提供了一个全面的景观,并强调了药物诱导的自噬在激活药物敏感性和逆转耐药方面的潜力。
UNASSIGNED: Autophagy plays important roles in cancer progression and therapeutic resistance, and the autophagy underlying the tumor pathogenesis and further mechanisms of chemoresistance emergence remains unknown.
UNASSIGNED: In this study, via the single-sample gene set enrichment analysis (ssGSEA) method, an autophagy 45-gene list was identified to evaluate samples\' autophagy activity, verified through six GEO datasets with a confirmed autophagy phenotype. It was further utilized to distinguish tumors into autophagy score-high and score-low subtypes, and analyze their transcriptome landscapes, including survival analysis, correlation analysis of autophagy- and resistance-related genes, biological functional enrichment, and immune- and hypoxia-related and genomic heterogeneity comparison, in TCGA pan-cancer datasets. Furthermore, we performed an analysis of autophagy status in breast cancer chemoresistance combined with multiple GEO datasets and in vitro experiments to validate the mechanisms of potential anticancer drugs for reversing chemoresistance, including CCK-8 cell viability assays, RT-qPCR, and immunofluorescence.
UNASSIGNED: The 45-gene list was used to identify autophagy score-high and score-low subtypes and further analyze their multi-dimensional features. We demonstrated that cancer autophagy status correlated with significantly different prognoses, molecular alterations, biological process activations, immunocyte infiltrations, hypoxia statuses, and specific mutational processes. The autophagy score-low subtype displayed a more favorable prognosis compared with the score-high subtype, associated with their immune-activated features, manifested as high immunocyte infiltration, including high CD8+T, Tfh, Treg, NK cells, and tumor-associated macrophages M1/M2. The autophagy score-low subtype also showed a high hypoxia score, and hypoxic tumors showed a significantly differential prognosis in different autophagy statuses. Therefore, \"double-edged\" cell fates triggered by autophagy might be closely correlated with the immune microenvironment and hypoxia induction. Results demonstrated that dysregulated autophagy was involved in many cancers and their therapeutic resistance and that the autophagy was induced by the resistance-reversing drug response, in five breast cancer GEO datasets and validated by in vitro experiments. In vitro, dihydroartemisinin and artesunate could reverse breast cancer doxorubicin resistance, through inducing autophagy via upregulating LC3B and ATG7.
UNASSIGNED: Our study provided a comprehensive landscape of the autophagy-related molecular and tumor microenvironment patterns for cancer progression and resistance, and highlighted the promising potential of drug-induced autophagy in the activation of drug sensitivity and reversal of resistance.