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MEMBRANE DYNAMICS

Tying lipid rafts to oncogenic signalling

Genetic amplifications and gain of function of growth factor signalling are among the most common drivers of cancer. Although it is widely accepted that local plasma membrane organization and lipid composition affect membrane-associated protein function, including signalling receptors, these links are generally poorly understood, and even more so in specific contexts such as cancer. Bi et al. now find that increased synthesis of saturated phospholipids and the formation of ordered lipid membrane domains support oncogenic growth factor signalling.

Credit: V. Summersby/Springer Nature Limited

Lipidomic analysis of a primary glioblastoma U87 cell line indicated that expression of a constitutively active epidermal growth factor receptor (EGFR) variant, EGFRvIII — a common driver of glioblastoma — caused membrane lipid remodelling. Specifically, the levels of saturated phosphatidylcholine (PC) species, produced by the activity of lysophosphatidylcholine acyltransferase 1 (LPCAT1), were increased. This increase was dependent on EGFRvIII signalling, which promoted LPCAT1 expression. In turn, LPCAT1 knockdown suppressed EGFR signalling, which was associated with increased internalization of EGFR from the plasma membrane; EGFR signalling could be restored by supplying saturated PC or its precursors. Thus, oncogenic EGFR signalling drives LPCAT1-mediated synthesis of saturated lipid species, which is required for EGFR residence at the plasma membrane and its sustained signalling.

Saturated membrane lipids promote the formation of ordered domains (lipid rafts). Consistent with its role in stimulating synthesis of saturated PC species, expression of EGFRvIII increased membrane order in U87 cells in a LPCAT1-dependent manner. Furthermore, EGFRvIII partitioned to ordered domains, suggesting that EGFRvIII signalling is augmented by receptor association with lipid rafts.

LPCAT1 depletion reduced cancer cell growth in the U87 cell line and patient-derived glioblastoma cells as well as in different cancer cell lines with LPCAT1 amplification (which has been detected in various cancers, in particular, highly aggressive tumours with poor patient prognosis). Moreover, LPCAT1 depletion inhibited growth of glioblastoma and LPCAT1-amplified tumours in mice.

“LPCAT1-mediated membrane lipid saturation … is an important mechanism driving oncogenic signalling”

In summary, LPCAT1-mediated membrane lipid saturation and subsequent ordering of the plasma membrane is an important mechanism driving oncogenic signalling and tumour growth. LPCAT1 could now be explored as a potential new drug target in oncology.

References

Original article

  1. Bi, J. et al. Oncogene amplification in growth factor signaling pathways renders cancers dependent on membrane lipid remodeling. Cell Metab. https://doi.org/10.1016/j.cmet.2019.06.014 (2019)

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Further reading

  1. Sezgin, E. et al. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat. Rev. Mol. Cell Biol. 18, 361–374 (2017)

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  2. Harayama, T. & Riezman, H. Understanding the diversity of membrane lipid composition. Nat. Rev. Mol. Cell Biol. 19, 281–296 (2018)

    CAS  Article  Google Scholar 

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Correspondence to Paulina Strzyz.

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Strzyz, P. Tying lipid rafts to oncogenic signalling. Nat Rev Mol Cell Biol 20, 513 (2019). https://doi.org/10.1038/s41580-019-0160-0

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  • DOI: https://doi.org/10.1038/s41580-019-0160-0

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