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

doi:10.1016/j.isci.2023.105962

Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity

iScience. 2023 Jan 13;26(2):105962. doi: 10.1016/j.isci.2023.105962. eCollection 2023 Feb 17.

Authors

Roberto Coppo¹, Jumpei Kondo¹, Keita Iida², Mariko Okada², Kunishige Onuma¹, Yoshihisa Tanaka^{3

4}, Mayumi Kamada⁵, Masayuki Ohue⁶, Kenji Kawada⁷, Kazutaka Obama⁷, Masahiro Inoue¹

Affiliations

¹ Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
³ Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
⁴ RIKEN Center for Computational Science, HPC- and AI-driven Drug Development Platform Division, Biomedical Computational Intelligence Unit, Hyogo, Japan.
⁵ Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁶ Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.
⁷ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.

Keywords: Cancer; Cell biology; Therapy.