Strength through diversity: how cancers thrive when clones cooperate.

Cancer is a highly heterogeneous disease, with many cancers containing multiple distinct subclones. While subclones are often seen as competitors (survival of the fittest), intratumor heterogeneity can also offer direct benefits to the tumor through cooperation between different clones. This has important clinical implications, as interdependent populations may present therapeutic vulnerabilities. Here, we review existing evidence for clonal cooperativity to address key questions and outline future developments based on six overarching principles: (a) secreted factors are important mediators of clonal cooperation; (b) (very) small subclones can significantly affect tumor behavior; (c) both genetic and nongenetic heterogeneity are substrates for cooperation; (d) nonmalignant cells from the tumor microenvironment can act as cooperating partners; (e) clonal cooperation occurs throughout different stages of cancer, from premalignancy to metastasis; and (f) clonal cooperation can promote therapy resistance by protecting otherwise sensitive populations. Together, these principles suggest clonal cooperation as an important mechanism in cancer. Lastly, we discuss how novel technological developments could address remaining gaps to open up new therapeutic strategies that exploit clonal cooperativity by targeting the tumor's weakest link.