Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole-tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors. We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification. The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers.

Berlin Institute of Health Berlin Germany

Central European Institute of Technology Department of Biology Faculty of Medicine Masarykova Univerzita Brno Czech Republic

Central European Institute of Technology Masarykova Univerzita Brno Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy Masarykova Univerzita Brno Czech Republic

Faculty of Medicine Digestive Oncology Unit Katholieke Universiteit Leuven Leuven Belgium

Faculty of Medicine Masarykova Univerzita Brno Czech Republic

German Cancer Research Center Heidelberg Germany

Institute of Pathology Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin Berlin Institute of Health Berlin Germany

Masaryk Memorial Cancer Institute Brno Czech Republic

RECETOX Faculty of Science Masarykova Univerzita Brno Czech Republic

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