1. Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling
- Author
-
Bi, Junfeng, Ichu, Taka-Aki, Zanca, Ciro, Yang, Huijun, Zhang, Wei, Gu, Yuchao, Chowdhry, Sudhir, Reed, Alex, Ikegami, Shiro, Turner, Kristen M, Zhang, Wenjing, Villa, Genaro R, Wu, Sihan, Quehenberger, Oswald, Yong, William H, Kornblum, Harley I, Rich, Jeremy N, Cloughesy, Timothy F, Cavenee, Webster K, Furnari, Frank B, Cravatt, Benjamin F, and Mischel, Paul S
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Cancer ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,1-Acylglycerophosphocholine O-Acyltransferase ,A549 Cells ,Animals ,Cell Survival ,ErbB Receptors ,Female ,Gene Amplification ,Gene Expression Regulation ,Neoplastic ,Genotype ,Heterografts ,Humans ,Mice ,Mice ,Nude ,Neoplasms ,Oncogenes ,PC-3 Cells ,Phospholipids ,Signal Transduction ,Transfection ,cancer dependency ,cancer metabolism ,gene amplification ,growth factor signaling ,membrane lipid remodeling ,Medical Biochemistry and Metabolomics ,Endocrinology & Metabolism ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - 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.
- Published
- 2019