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Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.

Publication ,  Journal Article
Di Conza, G; Tsai, C-H; Gallart-Ayala, H; Yu, Y-R; Franco, F; Zaffalon, L; Xie, X; Li, X; Xiao, Z; Raines, LN; Falquet, M; Jalil, A; Ho, P-C ...
Published in: Nature immunology
November 2021

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.

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Published In

Nature immunology

DOI

EISSN

1529-2916

ISSN

1529-2908

Publication Date

November 2021

Volume

22

Issue

11

Start / End Page

1403 / 1415

Related Subject Headings

  • X-Box Binding Protein 1
  • Tumor-Associated Macrophages
  • Tumor Microenvironment
  • Tumor Escape
  • Skin Neoplasms
  • STAT3 Transcription Factor
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phenotype
  • Mice, Transgenic
 

Citation

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Di Conza, G., Tsai, C.-H., Gallart-Ayala, H., Yu, Y.-R., Franco, F., Zaffalon, L., … Ho, P.-C. (2021). Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nature Immunology, 22(11), 1403–1415. https://doi.org/10.1038/s41590-021-01047-4
Di Conza, Giusy, Chin-Hsien Tsai, Hector Gallart-Ayala, Yi-Ru Yu, Fabien Franco, Lea Zaffalon, Xin Xie, et al. “Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.Nature Immunology 22, no. 11 (November 2021): 1403–15. https://doi.org/10.1038/s41590-021-01047-4.
Di Conza G, Tsai C-H, Gallart-Ayala H, Yu Y-R, Franco F, Zaffalon L, et al. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nature immunology. 2021 Nov;22(11):1403–15.
Di Conza, Giusy, et al. “Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.Nature Immunology, vol. 22, no. 11, Nov. 2021, pp. 1403–15. Epmc, doi:10.1038/s41590-021-01047-4.
Di Conza G, Tsai C-H, Gallart-Ayala H, Yu Y-R, Franco F, Zaffalon L, Xie X, Li X, Xiao Z, Raines LN, Falquet M, Jalil A, Locasale JW, Percipalle P, Masson D, Huang SC-C, Martinon F, Ivanisevic J, Ho P-C. Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity. Nature immunology. 2021 Nov;22(11):1403–1415.

Published In

Nature immunology

DOI

EISSN

1529-2916

ISSN

1529-2908

Publication Date

November 2021

Volume

22

Issue

11

Start / End Page

1403 / 1415

Related Subject Headings

  • X-Box Binding Protein 1
  • Tumor-Associated Macrophages
  • Tumor Microenvironment
  • Tumor Escape
  • Skin Neoplasms
  • STAT3 Transcription Factor
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phenotype
  • Mice, Transgenic