Mariluz Soula, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, Paul Bunk, Vishvak Subramanyam, Hsi Wen Yeh, Artem Khan, Søren Heissel, Hani Goodarzi, Gabriel D. Victora, Semir Beyaz, Kıvanç Birsoy
Research output: Contribution to journal › Article › peer-review
- Malignant Neoplasm Medicine and Dentistry 100%
- Glycosphingolipid Medicine and Dentistry 100%
- Immune Evasion Medicine and Dentistry 100%
- Glycosphingolipids Keyphrases 100%
- KRAS Biochemistry, Genetics and Molecular Biology 100%
- Cell Surface Immunology and Microbiology 100%
- Tumor Escape Immunology and Microbiology 100%
- Tumor Progression Medicine and Dentistry 50%
Soula, M., Unlu, G., Welch, R., Chudnovskiy, A., Uygur, B., Shah, V., Alwaseem, H., Bunk, P., Subramanyam, V., Yeh, H. W., Khan, A., Heissel, S., Goodarzi, H., Victora, G. D., Beyaz, S., & Birsoy, K. (2024). Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature, 633(8029), 451-458. https://doi.org/10.1038/s41586-024-07787-1
@article{2b7b7503e4214f778f8f5b27c17a2790,
title = "Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer",
abstract = "Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.",
author = "Mariluz Soula and Gokhan Unlu and Rachel Welch and Aleksey Chudnovskiy and Beste Uygur and Vyom Shah and Hanan Alwaseem and Paul Bunk and Vishvak Subramanyam and Yeh, {Hsi Wen} and Artem Khan and S{\o}ren Heissel and Hani Goodarzi and Victora, {Gabriel D.} and Semir Beyaz and Kıvan{\c c} Birsoy",
note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",
doi = "10.1038/s41586-024-07787-1",
publisher = "Nature Publishing Group",
}
Soula, M, Unlu, G, Welch, R, Chudnovskiy, A, Uygur, B, Shah, V, Alwaseem, H, Bunk, P, Subramanyam, V, Yeh, HW, Khan, A, Heissel, S, Goodarzi, H, Victora, GD, Beyaz, S & Birsoy, K 2024, 'Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer', Nature, vol. 633, no. 8029, pp. 451-458. https://doi.org/10.1038/s41586-024-07787-1
TY - JOUR
T1 - Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer
AU - Soula, Mariluz
AU - Unlu, Gokhan
AU - Welch, Rachel
AU - Chudnovskiy, Aleksey
AU - Uygur, Beste
AU - Shah, Vyom
AU - Alwaseem, Hanan
AU - Bunk, Paul
AU - Subramanyam, Vishvak
AU - Yeh, Hsi Wen
AU - Khan, Artem
AU - Heissel, Søren
AU - Goodarzi, Hani
AU - Victora, Gabriel D.
AU - Beyaz, Semir
AU - Birsoy, Kıvanç
N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/9/12
Y1 - 2024/9/12
N2 - Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
AB - Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
UR - http://www.scopus.com/inward/record.url?scp=85200695959&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-07787-1
DO - 10.1038/s41586-024-07787-1
M3 - Article
AN - SCOPUS:85200695959
SN - 0028-0836
VL - 633
SP - 451
EP - 458
JO - Nature
JF - Nature
IS - 8029
ER -