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Theoretical reasoning suggests that human cancer may result from knockingdown the genetic constraints evolved for maintenance of the metazoanmulticellularity, which, however, requires a critical test. Usingxenograft-based experimental evolution we characterized for the first time thefull life history from initiation to metastasis of a tumor at the genomic andtranscriptomic levels, and observed metastasis-driving positive selection forgenerally loss-of-function mutations on a set of multicellularity-relatedgenes, which is further supported by large-scale exome data of clinical tumorsamples. Subsequent expression analysis revealed mainly expressiondown-regulation of multicellularity-related genes, which form an evolvingexpression profile approaching that of embryonic stem cells, the cell type withthe most characteristics of unicellular life. The theoretical conjecturepredicts that genes born at the emergence of metazoan multicellularity tend tobe cancer drivers, which we validated using a rigorous phylostratigraphyanalysis on the birth rate of genes annotated by Cancer Gene Census. Also, thenumber of loss-of-function tumor suppressors often predominates over activatedoncogenes in a typical tumor of human patients. These data collectively suggestthat, different from typical organismal evolution in which gain of new genes isthe mainstream, cancer represents a loss-of-function-driven degenerativeevolution back to the unicellular ground state. This cancer evolution model mayexplain the enormous tumoral genetic heterogeneity in the clinic, underlie howdistant-organ metastases originate in primary tumors despite distinctenvironmental requirements, and hold implications for designing effectivecancer therapy.

The degenerative evolution from multicellularity to unicellularity during cancer