NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins.
NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins.
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DOI：
10.1158/2159-8290.cd-22-0043
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发表时间：
2022-09-02
期刊：
影响因子：
28.2
通讯作者：
Mancias, Joseph D.
中科院分区：
文献类型：
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作者：
Santana-Codina, Naiara;del Rey, Maria Quiles;Kapner, Kevin S.;Zhang, Huan;Gikandi, Ajami;Malcolm, Callum;Poupault, Clara;Kuljanin, Miljan;John, Kristen M.;Biancur, Douglas E.;Chen, Brandon;Das, Nupur K.;Lowder, Kristen E.;Hennessey, Connor J.;Huang, Wesley;Yang, Annan;Shah, Yatrik M.;Nowak, Jonathan A.;Aguirre, Andrew J.;Mancias, Joseph D.
NC 0A 4介导的铁蛋白的选择性自噬（“铁蛋白自噬”）在胰腺癌中上调以支持铁代谢用于肿瘤进展，从而代表新的治疗靶标。胰腺导管腺癌（PDAC）的生存依赖于自噬;然而，自噬提供的代谢底物驱动PDAC进展尚不清楚。铁蛋白是细胞铁储存复合物，通过选择性自噬衔接子NC 0A 4靶向溶酶体降解（铁蛋白吞噬），导致释放铁用于细胞利用。使用患者来源的PDAC和小鼠模型，我们证明PDAC中的铁蛋白吞噬上调以维持铁的可用性，从而促进肿瘤进展。定量蛋白质组学研究表明，铁蛋白吞噬促进铁硫簇蛋白的合成，以支持线粒体的稳态。靶向NCOA 4导致肿瘤生长延迟和生存期延长，但伴随着代偿性铁获得途径的发展。最后，增强的铁蛋白吞噬加速PDAC肿瘤发生，并且升高的铁蛋白吞噬表达特征预测PDAC患者的不良预后。总之，我们的数据表明，铁稳态的维持是PDAC自噬的关键功能，我们将NCOA 4介导的铁蛋白吞噬定义为PDAC的治疗靶点。自噬和铁代谢是PDAC的代谢依赖性。然而，缺乏针对这些途径的靶向治疗。我们鉴定了NC 0A 4介导的铁蛋白的选择性自噬（“铁蛋白自噬”）在PDAC中上调。铁蛋白吞噬支持PDAC铁代谢，从而支持肿瘤进展，并代表PDAC中的新治疗靶点。 见Jain和Amaravadi的相关评注，第2023页。 参见Ravichandran等人的相关文章，第2198页。 这篇文章在2007年的“本期专题”中突出显示
NCOA4-mediated selective autophagy of ferritin (“ferritinophagy”) is upregulated in pancreatic adenocarcinoma to support iron metabolism for tumor progression, thereby representing a new therapeutic target. 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. 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