Editors' ChoiceMetabolism

Cancer likes it saturated

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Science Translational Medicine  31 Jul 2019:
Vol. 11, Issue 503, eaay3580
DOI: 10.1126/scitranslmed.aay3580

Abstract

Constitutively active EGFR drives glioblastoma progression by overproducing saturated phosphatidylcholine.

Abnormalities in certain proteins can transform normal cells into cancerous ones. Some of those proteins, called receptor tyrosine kinases (RTKs), reside in the plasma membrane to transfer signals from outside the cell to inside. Once activated, the RTKs are phosphorylated, triggering downstream signaling cascades that drive cellular survival. Bi et al. found that saturated phosphatidylcholine (PC) regulates the physicochemical properties of the plasma membrane sustaining the activity of mutated epidermal growth factor receptor (EGFR), one of the commonly altered RTKs found in cancer.

PC is an integral component of the plasma membrane lipid bilayer. Unsaturated PC is continuously remodeled by removal of one of its fatty acid side chains through deacylation to generate lysophosphatidylcholine (LPC). Enzymes called lysophosphatidylcholine acyltransferases (LPCATs) then add back saturated fatty acid chains to form saturated PC species.

Using lipid metabolomics, Bi et al. found that a constitutively active form of EGFR increases saturated PC and decreased LPC and free fatty acids, suggesting higher activity of LPCAT1. In line with that, LPCAT1 protein was increased in glioblastoma tumor samples compared with normal brain tissue. In addition, LPCAT1 expression correlated with EGFR phosphorylation, a hallmark of tyrosine kinase activation. To test the codependency of LPCAT1 and EGFR, the authors genetically ablated LPCAT1 in glioblastoma cells and showed suppression of EGFR phosphorylation and downstream signaling. The authors then used imaging in live cells to demonstrate that mutated EGFR regulates plasma membrane architecture by altering its phospholipid composition in LPCAT1-dependent manner.

The researchers then used in vitro cell viability assays to show that targeting LPCAT1 is an effective antitumor approach in glioblastoma, as well as other cancer types. In those experiments, exogenous saturated—but not monounsaturated or polyunsaturated—PCs restored proliferation in LPCAT1-deficient cells. In subcutaneous xenografts, inducible genetic depletion of LPCAT1 reduced tumor growth, suggesting that LPCAT1 is a promising target to treat cancers harboring mutated EGFR.

In summary, this investigation showed that LPCAT1 and its product, saturated PC, are required for EGFR signaling. Targeted therapies against EGFR usually result in resistance through acquired mutations, making cancer harder to treat. Thus, finding alternative therapeutic targets such as LPCAT1 is clinically important. It is also worth investigating whether targeting LPCAT1 in combination with EGFR inhibitors can reduce the emergence of resistance.

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