Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

Automated summary

We demonstrate that asymmetric division of colorectal cancer stem-like cells (CCSCs) plays a critical role in the establishment of intratumor heterogeneity (ITH) at the early stage of tumor progression. Through single-cell RNA-seq and functional validation, we identify seven cell subtypes in CCSC-derived xenografts, three of which are generated by asymmetric division. These subtypes have distinct functions and appear early in the xenografts. We also investigate the regulators controlling the generation of a chemoresistant and an invasive subtype, and show that targeting these regulators can alter the composition of cell subtypes and affect CRC progression.