Pancreatic cancers require autophagy for tumor growth.

By Shenghong Yang, Xiaoxu Wang, G. Contino, M. Liesa, Ergun Sahin, Haoqiang Ying, Alexandra S. Bause, Yinghua Li, Jayne M. Stommel, G. Dell’Antonio and 7 more. Genes & Development, 2011

1,441 citations recorded by the source corpus.

Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.

Subfields: Epidemiology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9e9616e26eaca5fd53243b5b2711f8ec262bb3db

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In Epidemiology

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3. N. Mizushima
4. I. Slaninová
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In Molecular Biology

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In Oncology

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7. J. Joyce

Citations in the corpus

• Recent insights into the function of autophagy in cancer (2016, background): “Thus, in contrast to inhibition of general autophagy that blocks tumor progression (Wei et al. 2011; Yang et al. 2011; Guo et al. 2013a; Rosenfeldt et al. 2013; Strohecker et al. 2013), genetic deletion of two different mitophagy modulators (PARKIN and BNIP3) leads to increased tumorigenesis and…”
• Autophagy, Metabolism, and Cancer (2015, neutral): “Mechanismsof resistance to autophagy inhibition are unknown, although some human cancer cell lines are indifferent to ATG loss, indicating the existence of compensation mechanisms (36, 41, 87).”
• Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. (2011, result): “Indeed, autophagy is elevated in pancreatic cancer cell lines and tumors that display sensitivity to autophagy inhibition (Yang et al. 2011), consistent with the autophagy addiction model.”
• Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. (2015, neutral): “PDAC cells reuse the amino acids and fatty acids from these extracellular proteins and lipids to support growth, much as they also rely on recycling of intracellular materials via autophagy to survive metabolic stress (32, 33).”