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KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner
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DOI：10.1016/j.jlr.2026.101079.png)
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Abstract
En 中文
KRAS mutated at hotspots G12, G13 and Q61 possess profound allele-specific oncogenesis. Signaling of KRAS mutants is mostly compartmentalized to the proteolipid nanoclusters on the plasma membrane (PM), illustrating critical roles of spatiotemporal organization in KRAS cancer signaling. The activated GTP-bound KRAS molecules, including the wild-type and mutants, have been traditionally thought to favor similar lipids. We recently reported distinct lipid sensing capabilities of different KRAS mutants, especially with KRASG12D favoring unsaturated lipids and KRASG12C gaining additional enrichment of saturated lipids. As such, KRAS mutants may respond to lipid acyl chain remodeling in an allele-specific manner. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) facilitates the incorporation of saturated fatty acid chains to phospholipids. Here, we found that cells stably expressing LPCAT1 contain higher levels of saturated lipids and lower levels of unsaturated PS species. Electron microscopy (EM)–spatial analysis revealed that LPCAT1 expression disrupts the nanoclustering of KRASG12D on the PM, without affecting that of KRASG12C and HRASG12V. Elevation of LPCAT1 expression suppresses signaling, proliferation and colony formation of KRASG12D-expressing human pancreatic cancer cells, while promoting those of KRASG12C-expressing cells. Knocking out LPCAT1 depletes saturated lipids and reduces colony formation of KRASG12C cells. We further found that changing LPCAT1 expression specifically targets KRAS mutant-expressing cells, without affecting cells expressing wild-type KRAS. Mouse embryonic fibroblasts transformed with KRASG12C also contain more saturated lipids than KRASG12D MEFs. Thus, activities of KRAS mutants depends on lipid acyl chain remodeling in an allele-specific manner.
Keywords:
KRAS
nanoclustering
Lysophosphatidylcholine acyltransferase 1
phosphatidylserine
acyl chains,electron microscopy
cancer biology
phospholipids
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