Year: 2026
Type: article
Study design: Observational Study
Abstract: Circulating tumor DNA (ctDNA) is central to liquid biopsy-based cancer detection, yet the biological basis of its highly variable release into the bloodstream 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 stage I–III disease. ctDNA detectability increased with tumor burden, and ctDNA shedders exhibited a distinct architectural and microenvironmental phenotype characterized by expanded pseudolumina containing necrotic debris, frequent epithelial barrier disruption, and dense myeloid infiltration in lumina and stroma. Spatial profiling revealed stress-associated malignant programs and a myeloid-rich immune-luminal niche. In situ mutation detection localized plasma-identified mutations to necrotic material within pseudoluminal structures, establishing these compartments 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.
Source: Cell Death and Disease
Authors: Stefan Kühberger, Katja Sallinger, Christin-Therese Müller, Maria Escriva Conde, Sergio Marco Salas, Silvia Andaloro, Christine Beichler, Ricarda Graf, Karin Pankratz, Julia Enzi, Sarah Binder, Martina Scheiber, Lilli Bonstingl, Jasmin Blatterer, Stefan Uranitsch, Gabriele Moitzi, Hannes Schmölzer, Hubert Hauser, Karin Strohmeyer, Mats Nilsson, Sigurd Lax, Antonia Syrnioti, Rudolf Oehler, Gerald Hoefler, Felix Aigner, Amin El-Heliebi, Ellen Heitzer
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,990
OpenAlex ID: W7140222160