作者
Naiara Santana-Codina, Maria Quiles Del Rey, Kevin S Kapner, Huan Zhang, Ajami Gikandi, Callum Malcolm, Clara Poupault, Miljan Kuljanin, Kristen M John, Douglas E Biancur, Brandon Chen, Nupur K Das, Kristen E Lowder, Connor J Hennessey, Wesley Huang, Annan Yang, Yatrik M Shah, Jonathan A Nowak, Andrew J Aguirre, Joseph D Mancias
发表日期
2022/9/2
期刊
Cancer discovery
卷号
12
期号
9
页码范围
2180-2197
出版商
American Association for Cancer Research
简介
Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor NCOA4, resulting in release of iron for cellular utilization. Using patient-derived and murine models of PDAC, we demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability, thereby promoting tumor progression. Quantitative proteomics reveals that ferritinophagy fuels iron–sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with the development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated …
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N Santana-Codina, MQ Del Rey, KS Kapner, H Zhang… - Cancer discovery, 2022