Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer.
Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer.
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DOI：
10.1158/0008-5472.can-22-1039
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发表时间：
2022-12-02
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
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作者：
自噬是一个保守的分解代谢过程，维持细胞内稳态。自噬支持肺癌的发生，是肺癌治疗的一个潜在靶点。更好地理解肿瘤细胞自主性与系统性自噬在肺癌中的重要性可以促进自噬抑制的临床转化。在这里，我们利用Atg 5 shRNA的诱导表达来暂时控制Atg 5水平，并产生KrasG 12 D/+;p53−/−（KP）非小细胞肺癌（NSCLC）的可逆肿瘤特异性和系统性自噬丧失小鼠模型。短暂抑制全身而非肿瘤Atg 5表达显著降低了已建立的KP肺肿瘤生长，而不损害正常组织。在体内13 C同位素示踪和代谢通量分析表明，系统性Atg 5敲低具体导致葡萄糖和乳酸摄取减少。因此，在全身性自噬丧失后，KP NSCLC中从葡萄糖和乳酸到主要代谢途径（包括三羧酸循环、糖酵解和丝氨酸生物合成）的碳通量显著降低。此外，系统性Atg 5敲除增加肿瘤T细胞浸润，导致T细胞介导的肿瘤杀伤。重要的是，间歇性瞬时全身性Atg 5敲除（类似于癌症治疗中自噬抑制期间发生的情况）显著延长了KP肺肿瘤荷瘤小鼠的寿命，导致正常组织而非肿瘤的恢复。因此，系统性自噬通过促进免疫逃避和维持用于能量产生和生物合成的癌细胞代谢来支持已建立的肺肿瘤的生长，并且肿瘤不能从自噬丧失中恢复提供了抑制自噬是癌症治疗的有效方法的概念的进一步证据。
Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53−/− (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.
影响因子：
13.3
作者：
Cassidy LD;Young AR;Pérez-Mancera PA;Nimmervoll B;Jaulim A;Chen HC;McIntyre DJO;Brais R;Ricketts T;Pacey S;De La Roche M;Gilbertson RJ;Rubinsztein DC;Narita M
通讯作者：
Narita M