Association of APOBEC mutagenesis with stromal and endothelial niche remodeling and PCDH9-linked signaling alterations in colorectal cancer
Background APOBEC cytidine deaminases generate characteristic TCW-context mutations that diversify cancer genomes, yet their functional impact on colorectal cancer (CRC) progression and the tumor microenvironment (TME) remains poorly defined. Methods We integrated whole-exome sequencing, bulk and single-cell transcriptomics from multi-cohort datasets, supported by functional assays and in vivo xenograft models, to delineate the biological and clinical consequences of APOBEC activation in CRC. A machine-learning framework was used to derive an APOBEC activation–associated transcriptional signature (AAS). Results Across multi-cohort datasets, AAS defined a colorectal cancer subtype with enriched TCW mutagenesis and significantly worse survival. High AAS tumors were associated with coordinated remodeling of the TME, including increased fibroblast and endothelial signatures and reduced cytotoxic immune infiltration. Single-cell analyses suggested that high AAS tumors were enriched for endothelial states with arterial and pro-angiogenic features. Conditioned-medium experiments further supported a potential tumor cell secretome-mediated link between APOBEC3B activation and endothelial transcriptional remodeling. Integrative analyses identified PCDH9 as a candidate APOBEC-associated target linked to Hippo, Wnt/β-catenin, and TGF-β signaling alterations, while mutation-specific causality remains to be experimentally validated. Conclusions This multi-omics study identifies APOBEC activity as a central orchestrator of CRC evolution, associated with stromal-vascular remodeling and intracellular oncogenic activation through PCDH9-associated signaling alterations. The AAS provides a robust prognostic biomarker and highlights APOBEC-high tumors as candidates for anti-angiogenic therapy and for interventions targeting APOBEC-induced signaling vulnerabilities.