2. Academic Validation
  3. Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells

Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells

  • Antioxidants (Basel). 2025 Jul 7;14(7):833. doi: 10.3390/antiox14070833.
Marcella Bonanomi 1,  Sara Mallia 1 2,  Mariafrancesca Scalise 3,  Tecla Aramini 1,  Federica Baldassari 1 2,  Elisa Brivio 1 4,  Federica Conte 5,  Alessia Lo Dico 1 2,  Matteo Bonas 4,  Danilo Porro 2 4,  Cesare Indiveri 3 6,  Christian M Metallo 7,  Daniela Gaglio 1 2
Affiliations

Affiliations

  • 1 Institute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, Italy.
  • 2 National Biodiversity Future Center (NBFC), 90133 Palermo, PA, Italy.
  • 3 Unit of Biochemistry and Molecular Biotechnology, Department DiBEST (Biologia Ecologia Scienze della Terra), University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
  • 4 Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milano, MI, Italy.
  • 5 Institute for Systems Analysis and Computer Science "Antonio Ruberti" (IASI), National Research Council (CNR), 00185 Rome, RM, Italy.
  • 6 Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research Council (CNR), 70126 Bari, BA, Italy.
  • 7 Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
PMID: 40722937 DOI: 10.3390/antiox14070833
Abstract

Pancreatic Cancer is one of the most lethal malignancies, in part due to its profound metabolic adaptability, which underlies drug resistance and therapeutic failure. This study explores the metabolic rewiring associated with resistance to treatment using a systems metabolomics approach. Exposure to the redox-disrupting agent erastin revealed key metabolic vulnerabilities but failed to produce lasting growth suppression. Combinatorial treatments with methotrexate or alpelisib significantly impaired proliferation and triggered marked metabolic shifts. Systems-level analyses identified serine metabolism as a central adaptive pathway in resilient cells. Metabolic tracing and gene expression profiling showed increased de novo serine biosynthesis and uptake, supporting redox homeostasis, biosynthetic activity, and epigenetic regulation. Notably, cells that resumed growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways, along with elevated expression of genes linked to survival, proliferation, and migration. These findings establish serine metabolism as a functional biomarker of metabolic plasticity and adaptive resilience in pancreatic Cancer, suggesting that targeting this adaptive axis may enhance therapeutic efficacy.

Keywords

drug resistance; metabolic rewiring; pancreatic cancer; serine metabolism; targeted therapy.

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