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
Affiliations
Roberto Coppo
Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Jumpei Kondo
Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Keita Iida
Institute for Protein Research, Osaka University, Suita, Osaka, Japan
Mariko Okada
Institute for Protein Research, Osaka University, Suita, Osaka, Japan
Kunishige Onuma
Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Yoshihisa Tanaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; RIKEN Center for Computational Science, HPC- and AI-driven Drug Development Platform Division, Biomedical Computational Intelligence Unit, Hyogo, Japan
Mayumi Kamada
Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Masayuki Ohue
Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
Kenji Kawada
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Kazutaka Obama
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Masahiro Inoue
Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Corresponding author
Summary: 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.
