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Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma

Author

Listed:
  • Christel F. A. Ramirez

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Daniel Taranto

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Masami Ando-Kuri

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Marnix H. P. Groot

    (The Netherlands Cancer Institute)

  • Efi Tsouri

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Zhijie Huang

    (Sun Yat-sen University Cancer Center)

  • Daniel Groot

    (The Netherlands Cancer Institute)

  • Roelof J. C. Kluin

    (The Netherlands Cancer Institute)

  • Daan J. Kloosterman

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Joanne Verheij

    (University of Amsterdam)

  • Jing Xu

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute
    Sun Yat-sen University Cancer Center)

  • Serena Vegna

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Leila Akkari

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

Abstract

Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics’ specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.

Suggested Citation

  • Christel F. A. Ramirez & Daniel Taranto & Masami Ando-Kuri & Marnix H. P. Groot & Efi Tsouri & Zhijie Huang & Daniel Groot & Roelof J. C. Kluin & Daan J. Kloosterman & Joanne Verheij & Jing Xu & Seren, 2024. "Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46835-2
    DOI: 10.1038/s41467-024-46835-2
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