Faculty, Staff and Student Publications
Language
English
Publication Date
7-1-2026
Journal
Journal of Lipid Research
DOI
10.1016/j.jlr.2026.101079
PMID
42303154
PMCID
PMC13375922
PubMedCentral® Posted Date
6-16-2026
PubMedCentral® Full Text Version
Post-print
Abstract
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–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 WT 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
Proto-Oncogene Proteins p21(ras), Humans, Lipid Metabolism, Alleles, 1-Acylglycerophosphocholine O-Acyltransferase, Animals, Mutation, Mice/, KRAS, nanoclustering, lysophosphatidylcholine acyltransferase 1, phosphatidylserine, acyl chains, electron microscopy, cancer biology, phospholipids
Published Open-Access
yes
Recommended Citation
, "Kras G12C and Kras G12D Respond to Lipid Metabolism in an Allele-Specific Manner" (2026). Faculty, Staff and Student Publications. 181.
https://digitalcommons.library.tmc.edu/uthdb_docs/181