Transient Systemic Autophagy Inhibition Is Selectively and Irreversibly Deleterious to Lung Cancer

Author:

Khayati Khoosheh1ORCID,Bhatt Vrushank1ORCID,Lan Taijin1ORCID,Alogaili Fawzi1ORCID,Wang Wenping1ORCID,Lopez Enrique1ORCID,Hu Zhixian Sherrie1ORCID,Gokhale Samantha2ORCID,Cassidy Liam3ORCID,Narita Masashi3ORCID,Xie Ping12ORCID,White Eileen145ORCID,Guo Jessie Yanxiang167ORCID

Affiliation:

1. 1Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.

2. 2Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey.

3. 3University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge.

4. 4Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey.

5. 5Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, New Jersey.

6. 6Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.

7. 7Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey.

Abstract

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

Funder

National Cancer Institute

American Cancer Society

GO2 Foundation for Lung Cancer

Ludwig Princeton Branch of the Ludwig Institute for Cancer Research

New Jersey Commission on Cancer Research

Cox Foundation for Cancer Research

Mistletoe Research Fellowship

Cancer Research UK Cambridge Institute, University of Cambridge

Biotechnology and Biological Sciences Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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