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New mouse models of cancer: Single-cell knockouts

Cancer is a clonal disease, initiating from a single cell that has accumulated sufficient genetic damage to cause uncontrolled growth. The malignant daughter cells within a clone interact with each other and their normal neighboring cells, the so-called microenvironment, influencing tumor progression (1). The time required to clonally expand a single malignant cell to a clinically detectable tumor can take many years. During this time, other genetic changes occur, leading to the evolution of the tumor phenotype. One fundamental mechanism that triggers cancer formation is the mutation of tumor suppressor genes followed by loss of heterozygosity (2). Tumor suppressor gene mutations in the mouse have been used extensively to model human cancer (3). However, current mouse models, including germ-line mutations and tissue-specific knockouts, have not been able to reproduce the clonal nature of human cancer (Fig. 1 Left and Center). In this issue of PNAS, Muzumdar et al. (4) and Wang et al. (5) exploit genetic technologies modeled after systems in Drosophila to induce a second hit in a tumor suppressor gene in very few somatic cells in mice (Fig. 1 Right). The exciting findings show that the resulting few homozygous mutant cells surrounded by otherwise normal cells behave differently than in mice in which every cell of the body or a particular organ is mutant. The ability to generate clones of mutant cells and follow their behaviors (e.g., cell cycle status or tumor formation) in the mouse offers new opportunities to determine the cellular mechanisms of tumor formation and more accurately model human cancer.