| Autor: |
Dai E; Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, China., Han L; Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University , Changchun, Jilin, China., Liu J; The Third Affiliated Hospital, Guangzhou Medical University , Guangzhou, Guangdong, China., Xie Y; Department of Oncology, The Second Xiangya Hospital of Central South University , Changsha, Hunan, China., Kroemer G; Equipe Labellisée Par La Ligue Contre Le Cancer, Université De Paris, Sorbonne Université, INSERM U1138, Centre De Recherche Des Cordeliers , Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus , Villejuif, France.; Pôle De Biologie, Hôpital Européen Georges Pompidou , Paris, France.; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences , Suzhou, China.; Department of Women's and Children's Health, Karolinska University Hospital , Stockholm, Sweden., Klionsky DJ; Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan , Ann Arbor, Michigan, USA., Zeh HJ; Department of Surgery, UT Southwestern Medical Center , Dallas, Texas, USA., Kang R; Department of Surgery, UT Southwestern Medical Center , Dallas, Texas, USA., Wang J; Department of Respiratory Medicine, China-Japan Union Hospital of Jilin University , Changchun, Jilin, China., Tang D; The Third Affiliated Hospital, Guangzhou Medical University , Guangzhou, Guangdong, China.; Department of Surgery, UT Southwestern Medical Center , Dallas, Texas, USA. |
| Abstrakt: |
KRAS is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand the effects of KRAS mutation in cancer cells, the direct effects of the oncogenetic KRAS activation on immune cells remain elusive. Here, we report that extracellular KRAS G12D is essential for pancreatic tumor-associated macrophage polarization. Oxidative stress induces KRAS G12D protein release from cancer cells succumbing to autophagy-dependent ferroptosis. Extracellular KRAS G12D packaged into exosomes then is taken up by macrophages through an AGER-dependent mechanism. KRAS G12D causes macrophages to switch to an M2-like pro-tumor phenotype via STAT3-dependent fatty acid oxidation. Consequently, the disruption of KRAS G12D release and uptake can abolish the macrophage-mediated stimulation of pancreatic adenocarcinomas in mouse models. Importantly, the level of KRAS G12D expression in macrophages correlates with poor survival in pancreatic cancer patients. These findings not only identify extracellular KRAS G12D as a key mediator of cancer cell-macrophage communication, but also provide a novel KRAS-targeted anticancer strategy. Abbreviations: DAMP, damage-associated molecular pattern; PBMCMs, peripheral blood mononuclear cell-derived macrophages; PDAC, pancreatic ductal adenocarcinoma; s.c., subcutaneously; TAMs, tumor-associated macrophages; TME, tumor microenvironment. |
