Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells
Sunyoung Hwang,
H. Tobias Gustafsson,
Ciara O’Sullivan,
Gianna Bisceglia,
Xinhe Huang,
Christian Klose,
Andrej Schevchenko,
Robert C. Dickson,
Paola Cavaliere,
Noah Dephoure,
Eduardo M. Torres
Affiliations
Sunyoung Hwang
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
H. Tobias Gustafsson
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Ciara O’Sullivan
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Gianna Bisceglia
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Xinhe Huang
Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA
Christian Klose
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany
Andrej Schevchenko
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany
Robert C. Dickson
Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA
Paola Cavaliere
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA
Noah Dephoure
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA
Eduardo M. Torres
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid.
