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Gene expression dynamics in fibroblasts during early-stage murine pancreatic carcinogenesis

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal malignancies, characterized by aggressive local tumor growth and metastatic spread, in part driven by fibroblast-mediated stromal reactions in the tumor microenvironment. Early detection is critical for improved patient outcomes. In this study, we investigate the molecular cues within fibroblasts that offer promise for early PDAC diagnosis. We employ RNA sequencing of fibroblasts from KPC mouse models at pivotal time points, corresponding to the early preinvasive stages of pancreatic cancer. Our analysis reveals a substantial upregulation of gene sets associated with adipogenesis, fatty acid metabolism, and the ROS pathway in 12-week KPC-fibroblasts, indicative of metabolic reprogramming and redox regulation during early PDAC initiation. We narrow our focus to 26 potential key genes that may facilitate paracrine communication between fibroblasts and preneoplastic cells. Validation of our findings confirms the consistent increase in Angptl4, a gene linked to adipogenesis, and the notable downregulation of Lama2, a crucial extracellular matrix (ECM) gene. This study is the first to observe the elevation of Angptl4 in KPC-fibroblasts, providing essential insights into the role of fibroblasts in early PDAC. Moreover, our results hint at a potential role of fibroblasts in ECM degradation, a process that could support cancer cell proliferation and metastatic invasion. Genes associated with the ECM consistently display downregulation. These discoveries lay the foundation for future investigations into the mechanisms driving fibroblast-mediated elevation of Angptl4 and downregulation of ECM genes and their role in mediating crosstalk between fibroblast and preneoplastic cells. Our investigation into fibroblast transcriptional dynamics during early carcinogenesis offers significant potential for enhancing early diagnostic approaches in combating this deadly malignancy.

ORGANISM(S): Mus musculus

PROVIDER: GSE270121 | GEO | 2024/12/11

REPOSITORIES: GEO

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Project description:Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

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Gene expression dynamics in fibroblasts during early-stage murine pancreatic carcinogenesis

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