Evidence map›Paper›PMID 35771492›Full record

ArticleCancer discovery2022

NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins.

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 and 10 more

Abstract readComment
In one paragraph

Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers.

0numbers the graph read from it
0cells of the map it votes in
108citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

108 citing papers in PubMed.

  1. PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators.Journal of enzyme inhibition and medicinal chemistry · 2026
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48 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Naiara Santana-CodinaDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-8250-4530
Maria Quiles Del Rey *Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-7989-7193
Kevin S Kapner *Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-2306-2373
Huan Zhang *Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-3171-1385
Ajami GikandiDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-9556-106X
Callum MalcolmDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-5939-5452
Clara PoupaultDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-3145-9773
Miljan KuljaninDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-2157-2441
Kristen M JohnDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-1200-3386
Douglas E BiancurDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0001-8800-7124
Brandon ChenDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0002-6319-2228
Nupur K DasDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0002-5652-1134
Kristen E LowderDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0003-2615-4043
Connor J HennesseyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-5579-1220
Wesley HuangDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0003-0551-8397
Annan YangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-6750-0304
Yatrik M ShahDepartment of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.ORCID 0000-0002-2487-4816
Jonathan A NowakDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-0943-7407
Andrew J AguirreDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-0701-6203
Joseph D ManciasDivision of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-0692-3717

Funding

MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3M
Tissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI MAYER, ROBERT J · 2007 to 2023
$33.2M
Control of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7M
The role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2M
Cellular and Molecular Biology at MichiganT32GM145470 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI John Chadwick Brenner · 2022 to 2026
$4.1M
Systematic interrogation of the pancreatic cancer microenvironment in patient-derived specimensU01CA224146 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2017 to 2021
$3.0M
Development and implementation of multiplex methods to understand the biology and heterogeneity of patient-derived cancer modelsU01CA250549 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2020 to 2022
$2.9M
Understanding the mechanisms of iron addiction in colon cancerR01CA245546 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2020 to 2024
$2.3M
The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosisR01DK124384 · NIDDK · DANA-FARBER CANCER INST · PI MANCIAS, JOSEPH D · 2020 to 2024
$1.8M
Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancerK08CA218420 · NCI · DANA-FARBER CANCER INST · PI AGUIRRE, ANDREW JAMES · 2017 to 2021
$886k
NCI NIH HHS K08 CA218420NCI NIH HHS P50 CA127003NCI NIH HHS R01 CA148828NCI NIH HHS R01 CA245546NCI NIH HHS U01 CA224146NCI NIH HHS U01 CA250549NIDDK NIH HHS R01 DK095201NIDDK NIH HHS R01 DK124384NIGMS NIH HHS T32 GM007863NIGMS NIH HHS T32 GM145470
6 · The paper itself

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. SIGNIFICANCE: 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.

Indexed as

Carcinoma, Pancreatic DuctalIron-Sulfur ProteinsPancreatic NeoplasmsAnimalsAutophagyBiological AvailabilityFerritinsHumansIronMiceNuclear Receptor CoactivatorsSulfurTranscription FactorsFerritinsIronIron-Sulfur ProteinsNCOA4 protein, humanNcoA4 protein, mouseNuclear Receptor CoactivatorsSulfurTranscription Factors

Identifiers

PMID35771492
PMCPMC9437572

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.