EuroBioC2025 keynote presentation slides: Colorectal cancer through the lens of whole transcriptome imaging

Presented at the European Bioconductor Conference (EuroBioC2025) in Barcelona, September 2025.The transformation of normal intestinal epithelium into colorectal cancer (CRC) involves coordinated changes across molecular, cellular, and architectural scales; yet, how these layers integrate remains poorly resolved. Here, we survey colorectal tumorigenesis by combining whole-transcriptome spatial molecular imaging (WTx CosMx SMI) with single-nucleus RNA-sequencing (snPATHO-seq) and digital histopathology on colon samples containing reference mucosa, adenomas and carcinomas, as well as a metastatic lymph node. Leveraging (discrete) histological annotations and (continuous) data-driven trajectories, we quantify the dynamics of cellular density, heterogeneity, function and signaling along the reference-adenoma–carcinoma axis, which is concordant in its spatial and molecular definition. This combination of analytical approaches across different data views let us chart tissue transformation across dimensions (physical/transcriptional) and scales (cell/tissue). We resolve ∼3.5 million cells into 43 epithelial, immune, and stromal subpopulations that exhibit a bi-furcating tumor evolution: On the one hand, LGR5+ stem-like epithelial cells are enriched in highly homogeneous proliferative tumor cores. On the other hand, MMP7+ fetal-like states are restricted to immunosuppressive invasive fronts, rich in cancer-associated fibroblasts (CAFs) and tumor-associated macrophages. These subpopulations form concentric spatial layers that organize transformed regions, and their compound aligns with histological malignancy. We further define ‘transition crypts’ – single colonic crypts with divided histological and transcriptional makeup – that arise from rare crypt fusion or abrupt transformation events. Finally, we trace MMP7+ fetal-like tumor cell states and concomitant myofibroblast-like FAP+ CAFs to lymphovascular invasion sites and matched lymph node metastases, thereby recapitulating invasive programs at single-cell resolution and across sites. In all, we present single cell- and WTx-resolved spatial data that are among the first of their kind. These open up spatial-centric, out-of-the-box analytical avenues to resolve the molecular, cellular and architectural dynamics that attend tissue transformation during CRC onset, progression and dissemination.