Tissue architecture and immune niches govern ctDNA release in colorectal cancer
Kuehberger, S.; Sallinger, K.; Mueller, C.-T.; Escriva-Conde, M.; Marco-Salas, S.; Andaloro, S.; Beichler, C.; Graf, R.; Pankratz, K.; Enzi, J.; Binder, S.; Scheiber, M.; Bonstingl, L.; Blatterer, J.; Uranitsch, S.; Moitzi, G.; Schmoelzer, H.; Hauser, H.; Strohmeyer, K.; Nilsson, M.; Lax, S.; Syrnioti, A.; Oehler, R.; Hoefler, G.; Aigner, F.; El-Heliebi, A.; Heitzer, E.
Show abstract
Circulating tumor DNA (ctDNA) is central to liquid biopsy-based cancer detection, yet its release into the bloodstream varies widely and remains poorly understood. To define the tissue-level determinants of ctDNA shedding in colorectal cancer (CRC), we integrated tumor-informed plasma sequencing with detailed histopathology, immunophenotyping, spatial transcriptomics, and in situ mutation detection in resectable stages (I-III). ctDNA detectability increased with tumor burden, and high ctDNA shedders exhibited a distinct architectural and microenvironmental phenotype characterized by expanded necrotic pseudolumina, frequent epithelial barrier disruption, and dense myeloid infiltration. Spatial profiling revealed stress-associated malignant programs and a myeloid-rich immune-luminal niche. In situ sequencing confirmed plasma-detected mutations within pseudoluminal debris, identifying these structures as focal reservoirs of shed DNA. These findings provide a mechanistic framework linking tissue architecture, immune remodelling, and spatially organized cell death to ctDNA release with implications for refining liquid biopsy applications.
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