Polyclonality and metabolic heterogeneity in a colorectal tumor model.

The monoclonal origin of cancer is widely accepted, although numerous studies suggest that some are of polyclonal origin. Loss of checkpoints in transformed cells gives rise to carcinomas comprising a wide diversity of cell types that fulfill distinct, even complementary, metabolic functions, contrasting with a hypothetical monoclonal origin. Here, using a intestinal tumor model, we show that, despite an identical genetic background, these tumors (1) comprise a conserved set of different metabolic-specialized clusters; (2) are always polyclonal and derive from several clones characterized by distinct metabolic specificity; (3) depend on motility of the founder clones for their growth; and (4) share metabolic needs similar to those of human cancers. In summary, our study indicates that, in this model, tumor formation always requires assembly between founder clones potentially providing distinct cellular functions, as visualized by their metabolic heterogeneity. Thus, this polyclonal assembly would constitute a critical step of tumor progression.