Share, but unequally: a plausible mechanism for emergence and maintenance of intratumour heterogeneity.

Intratumour heterogeneity (ITH), referring to the coexistence of different cell subpopulations in a single tumour, has been a major puzzle in cancer research for almost half a century. The lack of understanding of the underlying mechanism of ITH hinders progress in developing effective therapies for cancers. Based on the findings in a recent quantitative experiment on pancreatic cancer, we developed a general evolutionary model for one type of cancer, accounting for interactions between different cell populations through paracrine or juxtacrine factors. We show that the emergence of a stable heterogeneous state in a tumour requires an unequal allocation of paracrine growth factors (public goods) between cells that produce them and those that merely consume them. Our model provides a quantitative explanation of recent in vitro experimental studies in pancreatic cancer in which insulin-like growth factor II (IGF-II) plays the role of public goods. The calculated phase diagrams as a function of exogenous resources and fraction of growth factor producing cells show ITH persists only in a narrow range of concentration of exogenous IGF-II. Remarkably, maintenance of ITH requires cooperation among tumour cell subpopulations in harsh conditions, specified by lack of exogenous IGF-II, whereas surplus exogenous IGF-II elicits competition. Our theory also quantitatively accounts for measured in vivo tumour growth in glioblastoma multiforme (GBM). The predictions for GBM tumour growth as a function of the fraction of tumour cells are amenable to experimental tests. The mechanism for ITH also provides hints for devising efficacious therapies.