Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

Meri Rogava, Tyler J. Aprati, Wei Yu Chi, Johannes C. Melms, Clemens Hug, Stephanie H. Davis, Ethan M. Earlie, Charlie Chung, Sachin K. Deshmukh, Sharon Wu, George Sledge, Stephen Tang, Patricia Ho, Amit Dipak Amin, Lindsay Caprio, Carino Gurjao, Somnath Tagore, Bryan Ngo, Michael J. Lee, Giorgia ZanettiYiping Wang, Sean Chen, William Ge, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Goeffrey T. Gibney, Oliver J. Schmitz, Megan Sykes, Rémi J. Creusot, Thomas Tüting, Dirk Schadendorf, Martin Röcken, Thomas K. Eigentler, Andrei Molotkov, Akiva Mintz, Samuel F. Bakhoum, Semir Beyaz, Lewis C. Cantley, Peter K. Sorger, Sven W. Meckelmann, Alpaslan Tasdogan, David Liu, Ashley M. Laughney, Benjamin Izar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)433-447
Number of pages15
JournalNature Cancer
Volume5
Issue number3
Early online date29 Jan 2024
DOIs
StatePublished - Mar 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding

We sincerely thank S. H. Davis, who sadly passed away during the completion of this study, for her dedication to excellence in cancer biology research and her passion for conducting humane animal research. We also thank J. Doench (genome perturbation platform at the Broad Institute) for technical guidance on the in vivo CRISPR screen, A. V. Parent from UCSF for technical advice, and E. Choi, A. Hung, S.-H. Wilhelm and L. Hsiauo-Yun from Columbia University for technical advice. B.I. is supported by National Institute of Health grants R37CA258829, R01CA280414, R01CA266446 and U54CA274506 and by the Pershing Square Sohn Cancer Research Alliance Award, the Burroughs Wellcome Fund Career Award for Medical Scientists, a Tara Miller Melanoma Research Alliance Young Investigator Award, the Louis V. Gerstner, Jr. Scholars Program and the V Foundation Scholars Award. B.N. was supported by K00CA234950. M. Röcken is supported by Wilhelm-Sander-Stiftung (2020.100.1); DFG RO 764 15/2; Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Germany, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanyʼs Excellence Strategy EXC 2180-390900677. E.M.E. partially supported by NIH T32 (grant GM132083). L.C. is supported by NIH/NCI grant F30CA281104. S.F.B. is supported by Mark Foundation for Cancer Research (20-028-EDV), Oliver S. and Jennie R. Donaldson Charitable Trust, Mathers Foundation, CSHL Cancer Center Shared Resources (Animal and Histology Core Facilities) and acknowledges support by NCI Cancer Center Support grant P30CA045508. L.C.C. is supported by NCI R35 CA197588. This work was supported by NIH/NCI Cancer Center Support Grant P30CA013696 and MSTP training grant T32GM007367 (for MD/PHD Students). Metabolomics Workbench is supported by NIH grant U2C-DK119886 and OT2-OD030544 grants. The following illustrations were prepared using BioRender.com : Fig. , Fig. and Fig. .

FundersFunder number
MSTPOT2-OD030544, T32GM007367, U2C-DK119886
Oliver S. and Jennie R. Donaldson Charitable Trust
V Foundation Scholars AwardDFG RO 764 15/2, EXC 2180, 2020.100.1, K00CA234950
National Institutes of HealthU54CA274506, GM132083, R01CA266446, R01CA280414, R37CA258829
National Cancer InstituteF30CA281104
Burroughs Wellcome Fund
Cold Spring Harbor LaboratoryP30CA045508, R35 CA197588, P30CA013696
Pershing Square Sohn Cancer Research Alliance
Mark Foundation For Cancer Research20-028-EDV
Deutsche ForschungsgemeinschaftEXC 2180-390900677
Eberhard Karls Universität Tübingen

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