Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity

Intra-tumor heterogeneity is frequently observed in cancer patients, and it is associated with therapeutic resistance and disease relapse. However, its systematic assessment is still limited and often unfeasible. Here, we use a mathematical model of tumor progression to decipher how multiple clones emerge and organize into complex architectures. We found a trade-off between cancer cell alteration and proliferation rates that defines a transition between low and high heterogeneity, the latter characterized by branching tumor phylogenies. We predict the existence of observed and hidden intra-tumor heterogeneity, which challenges the correct estimation of intrinsic tumor complexity. Although the numbers of observed and hidden clones do not always correlate, we demonstrate that population frequencies of observed clones can be used to estimate the extent of hidden heterogeneity in both simulated and human tumors. The characterization of complex clonal architectures is a critical first step toward understanding their organizing principles and predicting their emergence.