2. Academic Validation
  3. Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

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

  • Nat Cancer. 2024 Jan 29. doi: 10.1038/s43018-023-00704-x.
Meri Rogava 1 2 3,  Tyler J Aprati # 4,  Wei-Yu Chi # 5 6 7,  Johannes C Melms 1 2 3,  Clemens Hug 8,  Stephanie H Davis 8,  Ethan M Earlie 5 6 7 9,  Charlie Chung 10,  Sachin K Deshmukh 11,  Sharon Wu 11,  George Sledge 11,  Stephen Tang 1 2 3,  Patricia Ho 1 2 3,  Amit Dipak Amin 1 2 3,  Lindsay Caprio 1 2 3,  Carino Gurjao 1 2 3 12,  Somnath Tagore 1 2 12,  Bryan Ngo 6,  Michael J Lee 13,  Giorgia Zanetti 3,  Yiping Wang 1 2 3 12,  Sean Chen 1 2 3,  William Ge 4,  Luiza Martins Nascentes Melo 14,  Gabriele Allies 14,  Jonas Rösler 14,  Goeffrey T Gibney 15,  Oliver J Schmitz 16,  Megan Sykes 3,  Rémi J Creusot 3,  Thomas Tüting 17,  Dirk Schadendorf 14,  Martin Röcken 18,  Thomas K Eigentler 19,  Andrei Molotkov 20,  Akiva Mintz 20,  Samuel F Bakhoum 21 22,  Semir Beyaz 10,  Lewis C Cantley 23,  Peter K Sorger 8,  Sven W Meckelmann 16,  Alpaslan Tasdogan 14,  David Liu 4,  Ashley M Laughney 5 6 7,  Benjamin Izar 24 25 26 27
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 2 Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • 3 Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • 6 Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 7 Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • 8 Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 9 Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 10 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • 11 Caris Life Sciences, Phoenix, AZ, USA.
  • 12 Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA.
  • 13 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 14 Department 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.
  • 15 Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
  • 16 Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
  • 17 Laboratory for Experimental Dermatology, Department of Dermatology, University of Magdeburg, Magdeburg, Germany.
  • 18 Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.
  • 19 Department of Dermatology, Venerology and Allergology, Charité University Hospital, Berlin, Germany.
  • 20 Department of Radiology, Columbia University Medical Center, New York, NY, USA.
  • 21 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 22 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 23 Dana - Farber Cancer Institute, Boston, MA, USA.
  • 24 Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. bi2175@cumc.columbia.edu.
  • 25 Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA. bi2175@cumc.columbia.edu.
  • 26 Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA. bi2175@cumc.columbia.edu.
  • 27 Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA. bi2175@cumc.columbia.edu.
  • # Contributed equally.
PMID: 38286827 DOI: 10.1038/s43018-023-00704-x
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.

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