{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Santana-Codina N"],"funding":["NIDDK NIH HHS","NCI NIH HHS","NIH","NIGMS NIH HHS"],"pagination":["2180-2197"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9437572"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(9)"],"pubmed_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 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 ferritinophagy expression signature predicts for poor prognosis in patients with PDAC. Together, our data reveal that the maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.<h4>Significance</h4>Autophagy and iron metabolism are metabolic dependencies in PDAC. However, targeted therapies for these pathways are lacking. We identify NCOA4-mediated selective autophagy of ferritin (\"ferritinophagy\") as upregulated in PDAC. Ferritinophagy supports PDAC iron metabolism and thereby tumor progression and represents a new therapeutic target in PDAC. See related commentary by Jain and Amaravadi, p. 2023. See related article by Ravichandran et al., p. 2198. This article is highlighted in the In This Issue feature, p. 2007."],"journal":["Cancer discovery"],"pubmed_title":["NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins."],"pmcid":["PMC9437572"],"funding_grant_id":["U01 CA250549","R01 DK095201","K08 CA218420-02","T32 GM007863","T32 GM145470","R01 CA148828","K08 CA218420","P50 CA127003","R01 DK124384","U01 CA224146","R01 CA245546"],"pubmed_authors":["Biancur DE","Kuljanin M","Hennessey CJ","Zhang H","Gikandi A","Yang A","Chen B","Del Rey MQ","Malcolm C","Mancias JD","Das NK","Santana-Codina N","John KM","Poupault C","Kapner KS","Huang W","Shah YM","Lowder KE","Aguirre AJ","Nowak JA"],"additional_accession":[]},"is_claimable":false,"name":"NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins.","description":"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 ferritinophagy expression signature predicts for poor prognosis in patients with PDAC. Together, our data reveal that the maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.<h4>Significance</h4>Autophagy and iron metabolism are metabolic dependencies in PDAC. However, targeted therapies for these pathways are lacking. We identify NCOA4-mediated selective autophagy of ferritin (\"ferritinophagy\") as upregulated in PDAC. Ferritinophagy supports PDAC iron metabolism and thereby tumor progression and represents a new therapeutic target in PDAC. See related commentary by Jain and Amaravadi, p. 2023. See related article by Ravichandran et al., p. 2198. This article is highlighted in the In This Issue feature, p. 2007.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Sep","modification":"2025-04-04T10:58:28.781Z","creation":"2025-04-04T10:58:28.781Z"},"accession":"S-EPMC9437572","cross_references":{"pubmed":["35771492"],"doi":["10.1158/2159-8290.CD-22-0043"]}}