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Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.
Rogava, Meri; Aprati, Tyler J; Chi, Wei-Yu; Melms, Johannes C; Hug, Clemens; Davis, Stephanie H; Earlie, Ethan M; Chung, Charlie; Deshmukh, Sachin K; Wu, Sharon; Sledge, George; Tang, Stephen; Ho, Patricia; Amin, Amit Dipak; Caprio, Lindsay; Gurjao, Carino; Tagore, Somnath; Ngo, Bryan; Lee, Michael J; Zanetti, Giorgia; Wang, Yiping; Chen, Sean; Ge, William; Melo, Luiza Martins Nascentes; Allies, Gabriele; Rösler, Jonas; Gibney, Goeffrey T; Schmitz, Oliver J; Sykes, Megan; Creusot, Rémi J; Tüting, Thomas; Schadendorf, Dirk; Röcken, Martin; Eigentler, Thomas K; Molotkov, Andrei; Mintz, Akiva; Bakhoum, Samuel F; Beyaz, Semir; Cantley, Lewis C; Sorger, Peter K; Meckelmann, Sven W; Tasdogan, Alpaslan; Liu, David; Laughney, Ashley M; Izar, Benjamin.
Afiliación
  • Rogava M; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Aprati TJ; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Chi WY; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Melms JC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Hug C; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Davis SH; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Earlie EM; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Chung C; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Deshmukh SK; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Wu S; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Sledge G; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Tang S; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Ho P; Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • Amin AD; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Caprio L; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
  • Gurjao C; Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, USA.
  • Tagore S; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Ngo B; Caris Life Sciences, Phoenix, AZ, USA.
  • Lee MJ; Caris Life Sciences, Phoenix, AZ, USA.
  • Zanetti G; Caris Life Sciences, Phoenix, AZ, USA.
  • Wang Y; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Chen S; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Ge W; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Melo LMN; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Allies G; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Rösler J; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Gibney GT; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Schmitz OJ; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Sykes M; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Creusot RJ; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Tüting T; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Schadendorf D; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Röcken M; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Eigentler TK; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Molotkov A; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Mintz A; Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA.
  • Bakhoum SF; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Beyaz S; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Cantley LC; Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA.
  • Sorger PK; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Meckelmann SW; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • Tasdogan A; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
  • Liu D; Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • Laughney AM; Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos School of Physicians and Surgeons, New York, NY, USA.
  • Izar B; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.
Nat Cancer ; 5(3): 433-447, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38286827
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-akt / Neoplasias Hepáticas Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Proto-Oncogénicas c-akt / Neoplasias Hepáticas Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido