Cancers are currently diagnosed, categorised, and treated based on their tissue of origin. However, how different cellular compartments of tissues (e.g., epithelial, immune and stem cells) are similar across cancer types is unknown. Here we used colorectal cancer subtypes and their signatures representing different colonic crypt cell types as surrogates to classify different epithelial cancers into five heterotypic cellular (heterocellular) subtypes. The stem-like and inflammatory heterocellular subtypes are ubiquitous across epithelial cancers so capture intrinsic, tissue-independent properties. Conversely, well-differentiated/specialized goblet-like/enterocyte heterocellular subtypes differ across cancer types due to their colorectum-specific genes. The transit-amplifying heterocellular subtype shows a dynamic range of cellular differentiation with shared common pathways (Wnt, FGFR) in certain cancer types. Importantly, this approach revealed previously unrecognised heterogeneity in pancreatic, breast, microsatellite-instability enriched and KRAS mutation-dependent cancers. Immune cell-type differences are common and useful for patient stratification for immunotherapy. This unique approach identifies cell type-dependent but tissue-independent heterogeneity in different cancers for precision medicine.

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