@article{a28bb9e713c245ba9bc4288c4bfbccfd,
title = "Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling",
abstract = "Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers. Persistent growth factor receptor signaling and metabolic reprograming are hallmarks of cancer. Bi et al. show that LPCAT1-mediated phospholipid remodeling supports the sustained oncogenic activity of growth factor receptors on plasma membrane of tumor cells, suggesting an actionable dependency in a wide variety of cancers.",
keywords = "cancer dependency, cancer metabolism, gene amplification, growth factor signaling, membrane lipid remodeling",
author = "Junfeng Bi and Ichu, {Taka Aki} and Ciro Zanca and Huijun Yang and Wei Zhang and Yuchao Gu and Sudhir Chowdhry and Alex Reed and Shiro Ikegami and Turner, {Kristen M.} and Wenjing Zhang and Villa, {Genaro R.} and Sihan Wu and Oswald Quehenberger and Yong, {William H.} and Kornblum, {Harley I.} and Rich, {Jeremy N.} and Cloughesy, {Timothy F.} and Cavenee, {Webster K.} and Furnari, {Frank B.} and Cravatt, {Benjamin F.} and Mischel, {Paul S.}",
note = "Funding Information: This work was supported by the Ludwig Institute for Cancer Research and grants from National Institute for Neurological Diseases and Stroke (NS73831), the Defeat GBM Program of the National Brain Tumor Society, the Ben and Catherine Ivy Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (H.I.K.), an award from the Sharpe/National Brain Tumor Society Research Program, and a Compute for the Cure Award from the Nvidia Foundation (P.S.M.) as well as the UCSD Neuroscience Microscopy Shared Facility grant (P30 NS047101). J.B. T.-A.I. C.Z. H.Y. Wei Zhang, Y.G. S.C. A.R. K.M.T. Wenjing Zhang, G.R.V. S.W. O.Q. B.F.C. and P.S.M. designed and performed experiments. H.I.K. W.H.Y. T.F.C. and F.B.F. provided samples or regents and intellectual input. J.N.R. and W.K.C. provided intellectual input. J.B. T.-A.I. Wei Zhang, S. I. O.Q. B.F.C. and P.S.M. analyzed and interpreted data. J.B. and P.S.M. wrote the manuscript. P.S.M is co-founder of Pretzel Therapeutics. He has equity and serves as a consultant for the company. P.S.M. also did a one-time consultation for Abide Therapeutics. Funding Information: This work was supported by the Ludwig Institute for Cancer Research and grants from National Institute for Neurological Diseases and Stroke ( NS73831 ), the Defeat GBM Program of the National Brain Tumor Society , the Ben and Catherine Ivy Foundation , the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (H.I.K.), an award from the Sharpe/National Brain Tumor Society Research Program, and a Compute for the Cure Award from the Nvidia Foundation (P.S.M.) as well as the UCSD Neuroscience Microscopy Shared Facility grant ( P30 NS047101 ). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "3",
doi = "10.1016/j.cmet.2019.06.014",
language = "English (US)",
volume = "30",
pages = "525--538.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}