Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity
Roberto Coppo, Jumpei Kondo, Keita Iida, Mariko Okada, Kunishige Onuma, Yoshihisa Tanaka, Mayumi Kamada, Masayuki Ohue, Kenji Kawada, Kazutaka Obama, Masahiro Inoue
Abstract
Dynamic changes in cell properties lead to intratumor heterogeneity; however, the mechanisms of nongenetic cellular plasticity remain elusive. When the fate of each cell from colorectal cancer organoids was tracked through a clonogenic growth assay, the cells showed a wide range of growth ability even within the clonal organoids, consisting of distinct subpopulations; the cells generating large spheroids and the cells generating small spheroids. The cells from the small spheroids generated only small spheroids (S-pattern), while the cells from the large spheroids generated both small and large spheroids (D-pattern), both of which were tumorigenic. Transition from the S-pattern to the D-pattern occurred by various extrinsic triggers, in which Notch signaling and Musashi-1 played a key role. The S-pattern spheroids were resistant to chemotherapy and transited to the D-pattern upon drug treatment through Notch signaling. As the transition is linked to the drug resistance, it can be a therapeutic target.