RESUMO
Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
Assuntos
Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Membranas Intracelulares/metabolismo , Ativação de Macrófagos , Melanoma/metabolismo , Lipídeos de Membrana/metabolismo , Neoplasias Cutâneas/metabolismo , Macrófagos Associados a Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Retículo Endoplasmático/ultraestrutura , Glucosilceramidase/metabolismo , Membranas Intracelulares/ultraestrutura , Melanoma/genética , Melanoma/ultraestrutura , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/ultraestrutura , Evasão Tumoral , Microambiente Tumoral , Macrófagos Associados a Tumor/ultraestrutura , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
The occurrence of radioresistance is a clinical obstacle to endometrial cancer (EC) treatment and induces tumor relapse. In this study, we found that tumor-associated macrophages (TAMs) enriched in EC specimens were determined to present an M2-like phenotype. In vitro, the coculture of M2-polarized macrophages significantly downregulated the radiosensitivity of EC cells by releasing exosomes. Hsa_circ_0001610 was found to be abundant in exosomes derived from M2-polarized macrophages (EXOs), and hsa_circ_0001610 knockdown eliminated the reduction effect of EXOs on the radiosensitivity of EC cells. The following mechanism research revealed that hsa_circ_0001610 functioned as the competing endogenous RNA of miR-139-5p, thereby upregulating cyclin B1 expression, which is a vital pusher of radioresistance in several types of cancer by regulating the cell cycle. Hsa_circ_0001610 overexpression reduced the radiosensitivity of EC cells, which was then reversed by miR-139-5p overexpression. In vivo, the promotion effect of EXOs on xenograft tumor growth in nude mice treated with irradiation was further reinforced after hsa_circ_0001610 overexpression. In conclusion, TAM-derived exosomes transferred hsa_circ_0001610 to EC cells, and the overexpressed hsa_circ_0001610 in EC cells released cyclin B1 expression through adsorbing miR-139-5p, thereby weakening the radiosensitivity of EC cells.
