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Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis.
Klemm, Florian; Möckl, Aylin; Salamero-Boix, Anna; Alekseeva, Tijna; Schäffer, Alexander; Schulz, Michael; Niesel, Katja; Maas, Roeltje R; Groth, Marie; Elie, Benelita T; Bowman, Robert L; Hegi, Monika E; Daniel, Roy T; Zeiner, Pia S; Zinke, Jenny; Harter, Patrick N; Plate, Karl H; Joyce, Johanna A; Sevenich, Lisa.
Afiliación
  • Klemm F; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • Möckl A; Ludwig Institute for Cancer Research, Lausanne, Switzerland.
  • Salamero-Boix A; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Alekseeva T; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Schäffer A; Biological Sciences, Faculty 15, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Schulz M; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Niesel K; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Maas RR; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Groth M; Biological Sciences, Faculty 15, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Elie BT; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
  • Bowman RL; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • Hegi ME; Ludwig Institute for Cancer Research, Lausanne, Switzerland.
  • Daniel RT; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Zeiner PS; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Zinke J; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Harter PN; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Plate KH; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Joyce JA; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Sevenich L; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Nat Cancer ; 2(10): 1086-1101, 2021 10.
Article en En | MEDLINE | ID: mdl-35121879
Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb-STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Factor Estimulante de Colonias de Granulocitos y Macrófagos / Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Cancer Año: 2021 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Factor Estimulante de Colonias de Granulocitos y Macrófagos / Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Cancer Año: 2021 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido