Overweight status drives early tumor microenvironment reprogramming in pancreatic ductal adenocarcinoma: a cell-type-resolved Bayesian hierarchical modeling and interactome analysis

Abstract

Obesity significantly increases the risk of pancreatic ductal adenocarcinoma, yet a comprehensive understanding of obesity-driven tumor microenvironment remodeling remains incomplete. We developed a cell-type-resolved transcriptomic model using bulk RNA sequencing data from the Clinical Proteomic Tumor Analysis Consortium cohort (n=140) stratified by body mass index. A custom functional gene signature database covering 65 immune and stromal cell types was manually constructed and validated through large-language model-assisted review. Cell-type-specific expression profiles were derived using BayesPrism deconvolution with matched single-cell RNA sequencing references, enabling high-resolution quantification of signature activity within each cell type. Body mass index-associated signatures were identified using a machine learning framework. Bulk pathway analysis showed deterioration of extracellular matrix homeostasis and primary immunodeficiency pathways with rising body mass index. Bayesian hierarchical modeling revealed cell-type-specific, non-linear dynamics: stromal populations in overweight individuals underwent coordinated extracellular matrix remodeling and inflammatory signaling that stabilized rather than intensified in obesity, while CD8-positive T cells showed dose-dependent activation progressing to chronic exhaustion. Spatial analysis showed that stromal-trapped CD8-positive T cells were positioned progressively closer to the cytokeratin-positive tumor boundary with rising body mass index. These findings establish overweight status as a critical tipping point in tumor microenvironment reprogramming, suggesting that early metabolic interventions may prevent irreversible microenvironmental deterioration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/721695v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1c56c76org.highwire.dtl.DTLVardef@53b7e2org.highwire.dtl.DTLVardef@4d7b86org.highwire.dtl.DTLVardef@e8d403_HPS_FORMAT_FIGEXP M_FIG C_FIG