Tumor-Associated Schwann Cell Remodeling under Metabolic Stress via Lactate Sensing Orchestrates Pancreatic Ductal Adenocarcinoma Development.
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE303767 | GEO | 2025/08/12
REPOSITORIES: GEO
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Project description:Tumor-Associated Schwann Cell Remodeling under Metabolic Stress via Lactate Sensing Orchestrates Pancreatic Ductal Adenocarcinoma Development.
| PRJNA1297641 | ENA
Project description:Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Using in vivo models of diabetes-driven pancreatic tumorigenesis and metabolomics analysis, we demonstrate that metabolic stress induced by DM promotes pancreatic cancer progression by remodeling tumor-associated Schwann cells (TASs), impairing CD8+ T cell function. We discover that Mettl16+ Cd276+ Nectin2+ Schwann cells play a crucial role in mediating the pro-carcinogenic effects of lactate. Remodeled METTL16+ Schwann cells secret immune evasion factors (CD276, NECTIN2), contributing to anti-PD1 resistance. Furthermore, rosuvastatin was identified in this study as a novel METTL16 inhibitor for pancreatic cancer under metabolic stress. In conclusion, our study underscores the critical role of lactate in the metabolic reprogramming of pancreatic cancer mediated by Schwann cell remodeling, revealing novel pathways for therapeutic intervention.
2025-08-12 | GSE278961 | GEO
Project description:Diabetes mellitus (DM) is a known risk factor for pancreatic cancer, but the underlying mechanisms remain elusive. Using in vivo models of diabetes-driven pancreatic tumorigenesis and metabolomics analysis, we demonstrate that metabolic stress induced by DM promotes pancreatic cancer progression by remodeling tumor-associated Schwann cells (TASs), impairing CD8+ T cell function. We discover that Mettl16+ Cd276+ Nectin2+ Schwann cells play a crucial role in mediating the pro-carcinogenic effects of lactate. Remodeled METTL16+ Schwann cells secret immune evasion factors (CD276, NECTIN2), contributing to anti-PD1 resistance. Furthermore, rosuvastatin was identified in this study as a novel METTL16 inhibitor for pancreatic cancer under metabolic stress. In conclusion, our study underscores the critical role of lactate in the metabolic reprogramming of pancreatic cancer mediated by Schwann cell remodeling, revealing novel pathways for therapeutic intervention.
2025-08-12 | GSE303766 | GEO
Project description:Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates [scRNA-seq]
| PRJNA1169835 | ENA
Project description:Background & aimsThe dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs.MethodsBy small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway.ResultsInhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.ConclusionsCollectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.
| S-EPMC11304550 | biostudies-literature
Project description:Tumor-associated Schwann cell remodeling under metabolic stress via lactate sensing orchestrates [ChIP-seq, MeRIP-seq, RNA-seq]
| PRJNA1297650 | ENA
Project description:We aimed to investigate the protumor mechanisms of platelets in pancreatic ductal adenocarcinoma (PDAC). Serum samples were collected from 656 PDAC patients and 3105 healthy people, and a Panx1 knockout tumor model and an adoptive platelet transfusion mouse model were established. We showed that the blood platelet counts were not significantly different between stage III/IV and stage I/II patients, while the number of the CD41+/CD62P+ platelets was significantly elevated in stage III/IV patients, indicating that CD41+/CD62P+ platelets are associated with a poor prognosis. Further analysis showed that a high level of CD41+/CD62P+ platelets was significantly correlated with microvascular invasion (P = 0.002), advanced 8th edition AJCC stage (P < 0.001), and a high CA19-9 level (P = 0.027) and independently predicted a poor prognosis for resectable I/II PDAC. Furthermore, we found significantly higher Panx1 expression in CD41+/CD62P+ platelets than in CD41+/CD62P- platelets in PDAC patients. Mechanistically, Panx1 was able to enhance IL-1β secretion in CD41+/CD62P+ platelets by phosphorylating p38 MAPK and consequently promoted the invasion and metastasis of PDAC cells. Finally, we synthesized a novel compound named PC63435 by the ligation of carbenoxolone (a Panx1 inhibitor) and PSGL-1 (a CD62P ligand). PC63435 specifically bound to CD41+/CD62P+ platelets, then blocked the Panx1/IL-1β pathway and reduced the proportion of CD41+/CD62P+ platelets, which suppressed PDAC tumor invasion and metastasis in vivo. These results demonstrated that the Panx1/IL-1β axis in CD41+/CD62P+ platelets enhanced PDAC cell malignancy and that this axis may be a promising target for PDAC therapy.
| S-EPMC10015141 | biostudies-literature
Project description:Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by a diverse tumor microenvironment. The heterogeneous cellular composition of PDAC makes it challenging to study molecular features of tumor cells using extracts from bulk tumor. The metabolic features in tumor cells from clinical samples are poorly understood, and their impact on clinical outcomes are unknown. Our objective was to identify the metabolic features in the tumor compartment that are most clinically impactful. Methods: A computational deconvolution approach using the DeMixT algorithm was applied to bulk RNASeq data from The Cancer Genome Atlas to determine the proportion of each gene's expression that was attributable to the tumor compartment. A machine learning algorithm designed to identify features most closely associated with survival outcomes was used to identify the most clinically impactful metabolic genes. Results: Two metabolic subtypes (M1 and M2) were identified, based on the pattern of expression of the 26 most important metabolic genes. The M2 phenotype had a significantly worse survival, which was replicated in three external PDAC cohorts. This PDAC subtype was characterized by net glycogen catabolism, accelerated glycolysis, and increased proliferation and cellular migration. Single cell data demonstrated substantial intercellular heterogeneity in the metabolic features that typified this aggressive phenotype. Conclusion: By focusing on features within the tumor compartment, two novel and clinically impactful metabolic subtypes of PDAC were identified. Our study emphasizes the challenges of defining tumor phenotypes in the face of the significant intratumoral heterogeneity that typifies PDAC. Further studies are required to understand the microenvironmental factors that drive the appearance of the metabolic features characteristic of the aggressive M2 PDAC phenotype.
| S-EPMC10643182 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.
| S-EPMC8305839 | biostudies-literature
Project description:PurposePancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease that develops relatively symptom-free and is therefore advanced at the time of diagnosis. The absence of early symptoms and effective treatments has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic targets.Experimental designWe investigated the metabolism of a panel of PDAC cell lines in culture and noninvasively in vivo with (1)H magnetic resonance spectroscopic imaging (MRSI) to identify noninvasive biomarkers and uncover potential metabolic targets.ResultsWe observed elevated choline-containing compounds in the PDAC cell lines and tumors. These elevated choline-containing compounds were easily detected by increased total choline (tCho) in vivo, in spectroscopic images obtained from tumors. Principal component analysis of the spectral data identified additional differences in metabolites between immortalized human pancreatic cells and neoplastic PDAC cells. Molecular characterization revealed overexpression of choline kinase (Chk)-α, choline transporter 1 (CHT1), and choline transporter-like protein 1 (CTL1) in the PDAC cell lines and tumors.ConclusionsCollectively, these data identify new metabolic characteristics of PDAC and reveal potential metabolic targets. Total choline detected with (1)H MRSI may provide an intrinsic, imaging probe-independent biomarker to complement existing techniques in detecting PDAC. The expression of Chk-α, CHT1, and CTL1 may provide additional molecular markers in aspirated cytological samples.
| S-EPMC4297549 | biostudies-literature