ArticleNature cancer2024
Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.
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Article in Nature cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15citing papers in PubMed
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- SGLT2 inhibitors and risk of distant metastasis in patients with breast cancer and type 2 diabetes: a target trial emulation with biological plausibility analysis.EClinicalMedicine · 2026Article
- Sulfotransferase signaling sustains fibroblast identity and antagonizes therapeutic cardiac reprogramming.Nature communications · 2026Article
- Orthosteric-allosteric dual inhibitors of PI5P4Kγ with potent antitumor activity in non-small cell lung cancer.Journal of advanced research · 2026Article
- Tuning insulin receptor signaling using de novo-designed agonists.Molecular cell · 2025Article
- Sleep disorders in hepatocellular carcinoma.World journal of gastrointestinal oncology · 2025Review
- Mechanisms of organotropism in breast cancer and predicting metastasis to distant organs using deep learning.Discover oncology · 2025Article
- Phosphoinositide kinases in cancer: from molecular mechanisms to therapeutic opportunities.Nature reviews. Cancer · 2025Review
- Metabolic landscape of disseminated cancer dormancy.Trends in cancer · 2025Review
- Regulation of metastatic organotropism.Trends in cancer · 2025Review
- Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.Basic research in cardiology · 2025Review
- SGLT2 Inhibitors in Combination Therapies for Tumors: A Novel Approach to Synergistic Treatment Strategies.Drug design, development and therapy · 2025Review
- Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.Science advances · 2024Article
- LRG1 and SDR16C5 protein expressions differ according to HPV status in oropharyngeal squamous cell carcinoma.Scientific reports · 2024Article
- Cancer Cells Hijack Physiologic Metabolic Signals to Seed Liver Metastasis.Cancer research · 2024Article
- Metastatic organotropism: a brief overview.Frontiers in oncology · 2024Review
Corrections and comments
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Authors and funding
45 authors at 13 institutions in 2 countries.
Meri RogavaDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Tyler J Aprati *Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Wei-Yu Chi *Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.ORCID 0000-0002-4617-7827
Johannes C MelmsDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-5410-6586
Clemens HugLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Stephanie H DavisLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Ethan M EarlieDepartment of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.ORCID 0000-0003-3039-9692
Charlie ChungCold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Sachin K DeshmukhCaris Life Sciences, Phoenix, AZ, USA.
Sharon WuCaris Life Sciences, Phoenix, AZ, USA.
George SledgeCaris Life Sciences, Phoenix, AZ, USA.
Stephen TangDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0001-5492-9796
Patricia HoDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Amit Dipak AminDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-2613-2082
Lindsay CaprioDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Carino GurjaoDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Somnath TagoreDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Bryan NgoMeyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Michael J LeeDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
Giorgia ZanettiColumbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-3194-0877
Yiping WangDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Sean ChenDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
William GeDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Luiza Martins Nascentes MeloDepartment for Dermatology, Venerology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, Research Center One Health, Essen, Germany.
Gabriele AlliesDepartment for Dermatology, Venerology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, Research Center One Health, Essen, Germany.
Jonas RöslerDepartment for Dermatology, Venerology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, Research Center One Health, Essen, Germany.
Goeffrey T GibneyGeorgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
Oliver J SchmitzApplied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
Megan SykesColumbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-4947-4376
Rémi J CreusotColumbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
Thomas TütingLaboratory for Experimental Dermatology, Department of Dermatology, University of Magdeburg, Magdeburg, Germany.ORCID 0000-0001-7146-0934
Dirk SchadendorfDepartment for Dermatology, Venerology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, Research Center One Health, Essen, Germany.
Martin RöckenDepartment of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
Thomas K EigentlerDepartment of Dermatology, Venerology and Allergology, Charité University Hospital, Berlin, Germany.
Andrei MolotkovDepartment of Radiology, Columbia University Medical Center, New York, NY, USA.
Akiva MintzDepartment of Radiology, Columbia University Medical Center, New York, NY, USA.
Samuel F BakhoumHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Semir BeyazCold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.ORCID 0000-0003-4730-4012
Lewis C CantleyDana - Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0002-1298-7653
Peter K SorgerLaboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-3364-1838
Sven W MeckelmannApplied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
Alpaslan TasdoganDepartment for Dermatology, Venerology and Allergology, University Hospital Essen, NCT West, Campus Essen, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, Research Center One Health, Essen, Germany.ORCID 0000-0003-2543-852X
David LiuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0003-0346-5033
Ashley M LaughneyDepartment of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.ORCID 0000-0001-9435-953X
Benjamin IzarDivision of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. bi2175@cumc.columbia.edu.ORCID 0000-0003-2379-6702
Columbia University Irving Medical Center · USEssen University Hospital · DECornell University · USDana-Farber Cancer Institute · USCaris Life Sciences (United States) · USHarvard University · USCold Spring Harbor Laboratory · USUniversity of Duisburg-Essen · DECharité - Universitätsmedizin Berlin · DEGeorgetown Lombardi Comprehensive Cancer CenterMemorial Sloan Kettering Cancer Center · USUniversity Hospital Magdeburg · DEUniversity of Tübingen · DE
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4MSingle-Cell Biology Shared ResourceP30CA045508 · NCI · COLD SPRING HARBOR LABORATORY · PI John Edward Moses · 1987 to 2026
$118.9MTumor Biology and Microenvironment ProgramP30CA013696 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI Parisa Tehranifar · 1985 to 2026
$115.3MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007367 · NIGMS · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI REINER, STEVEN L · 1985 to 2021
$25.1MNational Metabolomics Data Repository - nextgen Metabolomics WorkbenchU2CDK119886 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUBRAMANIAM, SHANKAR · 2018 to 2021
$12.7MRole of Phosphoinositides and Protein Kinases in the control of Cancer MetabolismR35CA197588 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI LEWIS C. CANTLEY · 2016 to 2026
$10.2MStudying the evolution of drug resistance in prostate cancer at the single cell levelU54CA274506 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Peter Alan Sims · 2023 to 2026
$9.1MTri-Institutional PhD Program in Computational Biology & MedicineT32GM132083 · NIGMS · WEILL MEDICAL COLL OF CORNELL UNIV · PI Doron Betel, Iman Hajirasouliha · 2020 to 2026
$3.6MProbing cytosolic nucleic acid sensing pathways in cancerR01CA256188 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI LAUGHNEY, ASHLEY MARIE · 2021 to 2025
$3.5MBiomedical Data Commons Workbench (BDCW)OT2OD030544 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUBRAMANIAM, SHANKAR · 2020 to 2024
$3.2MDissecting the impact of tumor-intrinsic chromosomal instability on the cancer ecosystemR01CA280572 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI JOHN BLENIS, Ashley Marie Laughney · 2023 to 2026
$2.9MMulti-cellular interactions defining the human brain metastatic nicheR01CA280414 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Benjamin Izar, Ashley Marie Laughney · 2023 to 2026
$2.8MNCI NIH HHS F30 CA281104NCI NIH HHS K00 CA234950NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA013696NCI NIH HHS P30 CA045508NCI NIH HHS R01 CA256188NCI NIH HHS R01 CA266446NCI NIH HHS R01 CA280414NCI NIH HHS R01 CA280572NCI NIH HHS R35 CA197588NCI NIH HHS R37 CA258829NCI NIH HHS U54 CA274506NIDDK NIH HHS U2C DK119886NIGMS NIH HHS T32 GM007367NIGMS NIH HHS T32 GM132083NIH HHS DP5 OD026395NIH HHS OT2 OD030544NIH HHS S10 OD032433
Abstract
Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.
Indexed as
Liver NeoplasmsProto-Oncogene Proteins c-aktAnimalsHumansInsulinMicePhosphatidylinositol 3-KinasesPhosphotransferases (Alcohol Group Acceptor)Signal TransductionInsulinPhosphatidylinositol 3-KinasesPhosphotransferases (Alcohol Group Acceptor)Pip4k2c protein, mouseProto-Oncogene Proteins c-akt
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