Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells
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...
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| Format: | Article |
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MDPI AG
2025-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/7/833 |
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| author | Marcella Bonanomi Sara Mallia Mariafrancesca Scalise Tecla Aramini Federica Baldassari Elisa Brivio Federica Conte Alessia Lo Dico Matteo Bonas Danilo Porro Cesare Indiveri Christian M. Metallo Daniela Gaglio |
| author_facet | Marcella Bonanomi Sara Mallia Mariafrancesca Scalise Tecla Aramini Federica Baldassari Elisa Brivio Federica Conte Alessia Lo Dico Matteo Bonas Danilo Porro Cesare Indiveri Christian M. Metallo Daniela Gaglio |
| author_sort | Marcella Bonanomi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-21376cec32814c50baf0afca0902a603 |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-21376cec32814c50baf0afca0902a6032025-08-20T03:36:10ZengMDPI AGAntioxidants2076-39212025-07-0114783310.3390/antiox14070833Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer CellsMarcella Bonanomi0Sara Mallia1Mariafrancesca Scalise2Tecla Aramini3Federica Baldassari4Elisa Brivio5Federica Conte6Alessia Lo Dico7Matteo Bonas8Danilo Porro9Cesare Indiveri10Christian M. Metallo11Daniela Gaglio12Institute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyUnit of Biochemistry and Molecular Biotechnology, Department DiBEST (Biologia Ecologia Scienze della Terra), University of Calabria, 87036 Arcavacata di Rende, CS, ItalyInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyInstitute for Systems Analysis and Computer Science “Antonio Ruberti” (IASI), National Research Council (CNR), 00185 Rome, RM, ItalyInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyDepartment of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milano, MI, ItalyNational Biodiversity Future Center (NBFC), 90133 Palermo, PA, ItalyUnit of Biochemistry and Molecular Biotechnology, Department DiBEST (Biologia Ecologia Scienze della Terra), University of Calabria, 87036 Arcavacata di Rende, CS, ItalyMolecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USAInstitute of Molecular Bioimaging and Complex Biological Systems (IBSBC), National Research Council (CNR), 20054 Segrate, MI, ItalyPancreatic 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.https://www.mdpi.com/2076-3921/14/7/833pancreatic cancerdrug resistanceserine metabolismmetabolic rewiringtargeted therapy |
| spellingShingle | Marcella Bonanomi Sara Mallia Mariafrancesca Scalise Tecla Aramini Federica Baldassari Elisa Brivio Federica Conte Alessia Lo Dico Matteo Bonas Danilo Porro Cesare Indiveri Christian M. Metallo Daniela Gaglio Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells Antioxidants pancreatic cancer drug resistance serine metabolism metabolic rewiring targeted therapy |
| title | Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells |
| title_full | Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells |
| title_fullStr | Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells |
| title_full_unstemmed | Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells |
| title_short | Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells |
| title_sort | serine driven metabolic plasticity drives adaptive resilience in pancreatic cancer cells |
| topic | pancreatic cancer drug resistance serine metabolism metabolic rewiring targeted therapy |
| url | https://www.mdpi.com/2076-3921/14/7/833 |
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