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Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer
Khoosheh Khayati1, Vrushank Bhatt1, Taijin Lan1
1Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
Abstract:
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 to 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 vivo13C 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.
Significance:
Transient loss of systemic autophagy causes irreversible damage to tumors by suppressing cancer cell metabolism and promoting antitumor immunity, supporting autophagy inhibition as a rational strategy for treating lung cancer. See related commentary by Gan, p. 4322.
Insights
Systemic autophagy inhibition, but not tumor-specific, significantly reduced lung cancer growth by impairing tumor metabolism and boosting anti-tumor immunity. Intermittent systemic autophagy loss prolonged survival in mice, supporting autophagy inhibition as a lung cancer therapy.
Area of Science:
- Cell Biology
- Cancer Research
- Immunology
Background:
- Autophagy is a cellular process crucial for homeostasis and implicated in lung cancer progression.
- Understanding the distinct roles of tumor-intrinsic versus systemic autophagy is vital for developing effective lung cancer therapies.
- Targeting autophagy presents a promising therapeutic strategy for non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To investigate the differential impact of tumor-specific versus systemic autophagy loss on KrasG12D/+;p53-/- (KP) NSCLC growth.
- To elucidate the metabolic and immunological consequences of systemic autophagy inhibition in established lung tumors.
- To evaluate the therapeutic potential of transient systemic autophagy inhibition in a preclinical lung cancer model.
Main Methods:
- Generation of inducible mouse models with reversible tumor-specific and systemic autophagy loss using Atg5 shRNA.
- In vivo 13C isotope tracing and metabolic flux analyses to assess metabolic reprogramming.
- Analysis of tumor immune cell infiltration and T-cell-mediated cytotoxicity.
- Evaluation of tumor growth dynamics and animal lifespan following intermittent systemic autophagy inhibition.
Main Results:
- Transient systemic Atg5 knockdown significantly reduced established KP lung tumor growth without harming normal tissues.
- Systemic autophagy loss led to decreased glucose and lactate uptake, impacting major metabolic pathways within tumors.
- Systemic Atg5 knockdown enhanced T-cell infiltration and promoted T-cell-mediated tumor killing.
- Intermittent systemic Atg5 knockdown prolonged survival in tumor-bearing mice, with tumors unable to recover.
Conclusions:
- Systemic autophagy supports lung tumor growth by sustaining cancer cell metabolism and promoting immune evasion.
- Transient systemic autophagy inhibition offers a viable therapeutic strategy for NSCLC by disrupting tumor metabolism and enhancing anti-tumor immunity.
- The inability of tumors to recover from systemic autophagy loss validates autophagy inhibition as a promising approach for cancer therapy.
