Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells [PANC-1]
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ABSTRACT:
PROVIDER: PRJNA1241820 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic cancer is one of the most lethal malignancies, partly due to its profound metabolic adaptability, which contributes to drug resistance and therapeutic failure. Understanding how pancreatic cancer cells reprogram their metabolism in response to treatment may uncover new therapeutic vulnerabilities. This study investigates the metabolic adaptations underlying resistance to drug treatment in pancreatic cancer using a systems metabolomics approach to explore novel biomarkers and therapeutic strategies. Methods: Eight human pancreatic cancer cell lines were analyzed to assess metabolic heterogeneity and drug response. Untargeted and isotope-labeled metabolomics were performed to evaluate metabolic rewiring before and after treatment with erastin, a redox-disrupting agent. Differential correlation analysis was applied to identify key metabolic nodes associated with treatment adaptation. Combinatorial treatments using FDA-approved drugs targeting glycolysis and one-carbon metabolism were tested. Multi-omics integration of metabolomics and transcriptomics data was conducted to elucidate mechanisms of resistance. Results: Pancreatic cancer cell lines exhibited marked metabolic heterogeneity, with differences in nutrient dependency and mitochondrial activity. Erastin treatment revealed metabolic vulnerabilities but failed to sustain long-term growth suppression. Combinatorial treatments of erastin with methotrexate or alpelisib significantly reduced proliferation and induced metabolic alteration. A systems-level analysis identified serine metabolism as a central adaptive pathway activated in resistant mechanism. Metabolic tracing and gene expression analyses revealed increased de novo serine biosynthesis and uptake, coupled with enhanced redox balancing and epigenetic regulation. Notably, cell lines that reactivated growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways. These adaptations were associated with increased expression of survival, proliferation and migration-related genes. Conclusions: This study demonstrates that pancreatic cancer cells rewire their metabolism in response to combinatorial drug treatment by activating serine synthesis and uptake. These metabolic adaptations sustain redox homeostasis, biosynthetic processes and transcriptional reprogramming, contributing to resistance mechanism. Serine metabolism emerges as a functional biomarker of metabolic plasticity and drug tolerance. These insights open new avenues for metabolism-based strategies to overcome resistance and advance precision therapy in pancreatic cancer.
2025-07-08 | GSE292891 | GEO
Project description:Serine-Driven Metabolic Plasticity Drives Adaptive Resilience in Pancreatic Cancer Cells [HPAF-2]
| PRJNA1241817 | ENA
Project description:Pancreatic cancer is one of the most lethal malignancies, partly due to its profound metabolic adaptability, which contributes to drug resistance and therapeutic failure. Understanding how pancreatic cancer cells reprogram their metabolism in response to treatment may uncover new therapeutic vulnerabilities. This study investigates the metabolic adaptations underlying resistance to drug treatment in pancreatic cancer using a systems metabolomics approach to explore novel biomarkers and therapeutic strategies. Methods: Eight human pancreatic cancer cell lines were analyzed to assess metabolic heterogeneity and drug response. Untargeted and isotope-labeled metabolomics were performed to evaluate metabolic rewiring before and after treatment with erastin, a redox-disrupting agent. Differential correlation analysis was applied to identify key metabolic nodes associated with treatment adaptation. Combinatorial treatments using FDA-approved drugs targeting glycolysis and one-carbon metabolism were tested. Multi-omics integration of metabolomics and transcriptomics data was conducted to elucidate mechanisms of resistance. Results: Pancreatic cancer cell lines exhibited marked metabolic heterogeneity, with differences in nutrient dependency and mitochondrial activity. Erastin treatment revealed metabolic vulnerabilities but failed to sustain long-term growth suppression. Combinatorial treatments of erastin with methotrexate or alpelisib significantly reduced proliferation and induced metabolic alteration. A systems-level analysis identified serine metabolism as a central adaptive pathway activated in resistant mechanism. Metabolic tracing and gene expression analyses revealed increased de novo serine biosynthesis and uptake, coupled with enhanced redox balancing and epigenetic regulation. Notably, cell lines that reactivated growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways. These adaptations were associated with increased expression of survival, proliferation and migration-related genes. Conclusions: This study demonstrates that pancreatic cancer cells rewire their metabolism in response to combinatorial drug treatment by activating serine synthesis and uptake. These metabolic adaptations sustain redox homeostasis, biosynthetic processes and transcriptional reprogramming, contributing to resistance mechanism. Serine metabolism emerges as a functional biomarker of metabolic plasticity and drug tolerance. These insights open new avenues for metabolism-based strategies to overcome resistance and advance precision therapy in pancreatic cancer.
2025-07-08 | GSE292890 | GEO
Project description:To maintain lineage-specific functions, cells must acquire and allocate nutrients across diverse cellular processes, even in metabolically-dysregulated environments. The mechanisms allowing CD8+ T cells to maintain immune function in perturbed environments are poorly understood. We find that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reorient translational programming, limiting nutrient demand while prioritizing stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors ATF4 and CEBPG jointly establish an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial anaplerosis. Despite diminished energetic capacity under environmental stress, this program prevents failure of central carbon metabolism, mitigating stress amplification and cellular dysfunction to potentiate anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers functional resilience to immune cells in unfavorable environments, offering novel strategies to enhance immunotherapies.
2026-05-05 | GSE287987 | GEO
Project description:The interplay between phenotypic plasticity and adaptive evolution has long been an important topic of evolutionary biology. This process is critical to our understanding of a species evolutionary potential in light of rapid climate changes. Despite recent theoretical work, empirical studies of natural populations, especially in marine invertebrates, are scarce. In this study, we investigated the relationship between adaptive divergence and plasticity by integrating genetic and phenotypic variation in Pacific oysters from its natural range in China. Genome resequencing of 371 oysters revealed unexpected fine-scale genetic structure that is largely consistent with phenotypic divergence in growth, physiology, thermal tolerance and gene expression across environmental gradient. These findings suggest that selection and local adaptation are pervasive and together with limited gene flow shape adaptive divergence. Plasticity in gene expression is positively correlated with evolved divergence, indicating that plasticity is adaptive and likely favored by selection in organisms facing dynamic environments such as oysters. Divergence in heat response and tolerance implies that the evolutionary potential to a warming climate differs among oyster populations. We suggest that trade-offs in energy allocation are important to adaptive divergence with acetylation playing a role in energy depression under thermal stress.
2018-07-27 | PXD008057 | Pride
Project description:An adaptive stress response that confers cellular resilience to decreased ubiquitination
| PRJNA918302 | ENA
Project description:To maintain lineage-specific functions, cells must acquire and allocate nutrients across diverse cellular processes, even in metabolically-dysregulated environments. The mechanisms allowing CD8+ T cells to maintain immune function in perturbed environments are poorly understood. We find that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reorient translational programming, limiting nutrient demand while prioritizing stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors ATF4 and CEBPG jointly establish an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial anaplerosis. Despite diminished energetic capacity under environmental stress, this program prevents failure of central carbon metabolism, mitigating stress amplification and cellular dysfunction to potentiate anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers functional resilience to immune cells in unfavorable environments, offering novel strategies to enhance immunotherapies.
2026-05-05 | GSE287894 | GEO
Project description:Analysis of differentially expressing genes in whole genome wide analysis of aptamer SQ2 positive cells (Capan-1, Panc-1, Panc-1+ve) and SQ2 negative cells (Panc-1-ve and HPDE) Panc-1 +ve and Panc-1-ve cell lines were generated from Panc-1 cell line based upon its hetergenous binding to aptamer SQ2. Detailed procedure of generation of these cell lines are described in Pooja Dua, Hye Suk Kang, Seung-Mo Hong, Ming-Sound Tsao, Soyoun Kim, and Dong-ki Lee. 2012 Alkaline Phosphatase ALPPL2 is a novel pancreatic carcinoma-associated protein. Cancer Research A five chip study using total RNA recovered from Capan-1, Panc-1, Panc-1+ve, Panc-1-ve and HPDE cells. Each chip measures 45,033 genes with three 60 mer probe pairs per target.
2012-11-21 | E-GEOD-42428 | biostudies-arrayexpress
Project description:Gemcitabine has been a first-line therapeutic agent for pancreatic ductal adenocarcinoma (PDAC) pancreatic cancer; however, acquisition of resistance to gemcitabine remains a major challenge. We analyzed miRNAs expression profiles by array-based miRNAs analysis between gemcitabine–resistant (PANC-1/GEM) and parental PANC-1 cells.
2016-12-31 | GSE79234 | GEO
Project description:Analysis of differentially expressing genes in whole genome wide analysis of aptamer SQ2 positive cells (Capan-1, Panc-1, Panc-1+ve) and SQ2 negative cells (Panc-1-ve and HPDE) Panc-1 +ve and Panc-1-ve cell lines were generated from Panc-1 cell line based upon its hetergenous binding to aptamer SQ2. Detailed procedure of generation of these cell lines are described in Pooja Dua, Hye Suk Kang, Seung-Mo Hong, Ming-Sound Tsao, Soyoun Kim, and Dong-ki Lee. 2012 Alkaline Phosphatase ALPPL2 is a novel pancreatic carcinoma-associated protein. Cancer Research
2012-11-21 | GSE42428 | GEO