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bioRxiv · 10.1101/2025.11.14.688523

A Pan-Cancer Blueprint of Early Tumor Microenvironment Reprogramming

Bhavya, B.·Agrawal, S.·Pathak, E.·Mishra, R.
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Abstract

Metabolic disruption is a defining early event in tumorigenesis, yet its coordination with transcriptional and inflammatory remodeling remains unclear. Across fourteen first-stage solid tumors, we integrate transcriptomic, metabolic, immune, microRNA, and network-topological analyses to construct a blueprint of early tumor microenvironment reprogramming. Gene-network evolution revealed preferential attachment of proliferative hubs (FOXM1, CDK1, CCNB1, CDC20, TOP2A) accompanied by loss of neighborhood connectivity in key metabolic regulators (PPARA, PPARG, PRKACA/B, CREB1, SRC), indicating early erosion of lipid sensing, oxidative restraint, and metabolic-neuronal signaling. Pathway analysis demonstrated consistent suppression of fatty acid degradation and PPAR signaling, establishing a shift toward anabolic growth. ADH1B was uniformly downregulated across all cancers, linking impaired aldehyde metabolism to redox stress and inflammatory activation. Integration of inflammatory and apoptotic modules highlighted recurrent IRG-AG pairs, including IL11-MMP9-FGF10, forming a conserved inflammation-apoptosis-metabolism axis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/688523v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@4648a0org.highwire.dtl.DTLVardef@4a2885org.highwire.dtl.DTLVardef@aa6940org.highwire.dtl.DTLVardef@1e41847_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINetwork evolution reveals "trigger genes" shaping early oncogenic transformation C_LIO_LIFOXM1 attachment and PPAR/CREB1 detachment coordinate metabolic reprogramming C_LIO_LIUniform ADH1B downregulation in 14 cancers links metabolic imbalance with inflammation C_LIO_LIIntegrated multi-omics uncovers a blueprint of early tumor-microenvironment shifts C_LI

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Bhavya, B., Agrawal, S., Pathak, E., Mishra, R.. 2025-11-16. A Pan-Cancer Blueprint of Early Tumor Microenvironment Reprogramming. https://doi.org/10.1101/2025.11.14.688523

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