Uncovering Tumorigenesis Circuitry with Combinatorial CRISPR

Oncogenesis relies on the alteration of multiple driver genes, but precisely which groups of alterations lead to cancer is not well understood. To chart these combinations, Zhao and colleagues use the CRISPR-Cas9 system to knockout all pairwise combinations among 52 tumor suppressor genes, with the goal of identifying groups of alterations that collaborate to promote cell growth. Interaction screens are performed across multiple models of tumorigenesis in cell cultures and mice, revealing clear cooperation among NF2, PTEN, and TP53 in multiple models. These and other strongly synergistic interactions are characterized further by single-cell transcriptomic profiling. This methodology presents a scalable approach to move beyond single-gene drivers to map the complex gene networks that give rise to tumorigenesis.See related article by Zhao et al., p. 6090.