Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling

Junfeng Bi, Taka Aki Ichu, Ciro Zanca, Huijun Yang, Wei Zhang, Yuchao Gu, Sudhir Chowdhry, Alex Reed, Shiro Ikegami, Kristen M. Turner, Wenjing Zhang, Genaro R. Villa, Sihan Wu, Oswald Quehenberger, William H. Yong, Harley I. Kornblum, Jeremy N. Rich, Timothy F. Cloughesy, Webster K. Cavenee, Frank B. FurnariBenjamin F. Cravatt, Paul S. Mischel

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)525-538.e8
JournalCell Metabolism
Volume30
Issue number3
DOIs
StatePublished - Sep 3 2019
Externally publishedYes

Keywords

  • cancer dependency
  • cancer metabolism
  • gene amplification
  • growth factor signaling
  • membrane lipid remodeling

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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