2. Academic Validation
  3. Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction

Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction

  • Mol Cell. 2026 Mar 5;86(5):901-916.e10. doi: 10.1016/j.molcel.2026.02.002.
Miriam Lisci 1,  Fanny Vericel 1,  Yifan Liu 2,  Hector Gallart-Ayala 3,  Julijana Ivanisevic 3,  Owen S Skinner 2,  Alexis A Jourdain 4
Affiliations

Affiliations

  • 1 Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, 1066 Epalinges, Switzerland.
  • 2 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • 3 Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, 1005 Lausanne, Switzerland.
  • 4 Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: [email protected].
PMID: 41747732 DOI: 10.1016/j.molcel.2026.02.002
Abstract

Metabolic flexibility is key to survival and growth in all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although certain tumors display metabolic dependencies that can be targeted for therapy. Here, we combine metabolic tracers, nutrient supplementation, and genome-wide CRISPR-Cas9 screening to investigate the pathways mediating glutamine addiction, a hallmark of several cancers. We report that the vitamin biotin allows the bypassing of glutamine dependence by activating pyruvate carboxylase (PC), and we discover a mechanism by which the tumor suppressor FBXW7 promotes pyruvate anaplerosis. Mechanistically, we show that FBXW7 prevents c-Myc accumulation and recruitment of a cluster of transcriptional repressors, including MAX, MNT, and SIN3A, to the PC promoter, thereby maintaining PC expression and avoiding glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility and prevent glutamine addiction in Cancer, with high relevance for FBXW7-associated Cancer mutations.

Keywords

FBXW7; MYC; PC; biotin; glutamine; glutamine addiction; malate-aspartate shuttle; nutrient screen; pyruvate; pyruvate carboxylase.

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