Title |
NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron–Sulfur Cluster Proteins
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Published in |
Cancer Discovery, June 2022
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DOI | 10.1158/2159-8290.cd-22-0043 |
Pubmed ID | |
Authors |
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 |
Abstract |
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 now 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 development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in PDAC patients. Together, our data reveal that maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC. |
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Country | Count | As % |
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United States | 24 | 43% |
Spain | 4 | 7% |
Germany | 2 | 4% |
United Kingdom | 1 | 2% |
Mexico | 1 | 2% |
Cyprus | 1 | 2% |
Unknown | 23 | 41% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 30 | 54% |
Scientists | 22 | 39% |
Science communicators (journalists, bloggers, editors) | 3 | 5% |
Practitioners (doctors, other healthcare professionals) | 1 | 2% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 24 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 3 | 13% |
Lecturer > Senior Lecturer | 2 | 8% |
Student > Bachelor | 2 | 8% |
Researcher | 2 | 8% |
Student > Doctoral Student | 1 | 4% |
Other | 5 | 21% |
Unknown | 9 | 38% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 8 | 33% |
Medicine and Dentistry | 3 | 13% |
Unspecified | 1 | 4% |
Social Sciences | 1 | 4% |
Agricultural and Biological Sciences | 1 | 4% |
Other | 2 | 8% |
Unknown | 8 | 33% |