Abstract
p53 status determines whether autophagy promotes or inhibits pancreatic cancer in mice.
Major finding: p53 status determines whether autophagy promotes or inhibits pancreatic cancer in mice.
Clinical relevance: Inhibiting autophagy in p53-negative cells accelerated the development of pancreatic tumors.
Impact: p53 status should be considered when autophagy inhibitors are used as cancer therapies.
Autophagy, an essential homeostatic process by which cells degrade and recycle cytoplasmic components, has been implicated in both tumor suppression and tumorigenesis depending on the cancer type and context. The molecular determinants that dictate the effect of autophagy on tumor progression have not been defined. Rosenfeldt and colleagues identified the tumor suppressor p53 as a regulator of whether autophagy suppresses or promotes cancer in a Kras-driven mouse model of pancreatic ductal adenocarcinoma (PDAC). Pancreatic-specific expression of constitutively active Kras (KrasG12D) induces the formation of precancerous lesions that stochastically progress to PDAC. However, in KrasG12D mice also lacking the essential autophagy gene Atg7, precancerous lesions accumulated but never progressed to PDAC, suggesting a requirement for autophagy in tumor progression. These lesions exhibited elevated p53 levels, expression of senescence markers, and sustained growth arrest. Because p53 is inactivated in 50% of human PDAC, the role of autophagy in pancreatic tumor progression was examined in KrasG12D mice also lacking p53. Although tumor formation occurred irrespective of Atg7 status, KrasG12D;Atg7−/−;Trp53−/− mice exhibited a reduced life span due to accelerated formation of PDAC, indicative of a tumor-suppressive role for autophagy in the absence of p53. Consistent with these findings, treatment of KrasG12D;Atg7+/+;Trp53−/− mice with hydroxychloroquine, an autophagy inhibitor currently being evaluated as a potential cancer therapy in clinical trials, similarly accelerated PDAC formation. Furthermore, PDAC cells grown from KrasG12D;Atg7+/+;Trp53−/− mice showed an irreversible increase in glucose uptake and enhanced anabolic intermediates not observed in autophagy-competent counterparts, correlating with the more aggressive nature of these tumors. Although further investigation of the mechanisms by which p53 switches the requirement for autophagy in tumor progression is warranted, these results underscore the complexity of targeting autophagy and raise the possibility that autophagy inhibitors may be contraindicated for patients with p53-deficient cancers.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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