Title:

Organoid Models for Reconstitution of Carcinogenesis and Implementation of Precision Medicine

 

Speaker:

Yoshitaka Hippo, MD PhD

Department of Molecular Carcinogenesis, Chiba Cancer Center Research Institute

 

Abstract:

Accumulated mutations and tissue-specific microenvironments cooperate for carcinogenesis. Whereas genetically engineered mice have been widely used to physiologically model such process, we previously demonstrated that an organoid-based ex vivo approach could pave an alternative way to promptly recapitulate multi-step colorectal tumorigenesis (Onuma et al, PNAS 2013). Specifically, we conducted in vitro reconstitution of genetic aberrations in murine intestinal organoids under our Matrigel bilayer organoid culture (MBOC) protocol (Maru et al, Cancer Sci 2019), and subsequently inoculated the transduced organoids into nude mice. With this ex vivo approach, we further demonstrated that the tumorigenesis driven by diverse mutations were considerably mimicked for many organs, including lung (Sato et al, Oncol Lett 2017), hepatobiliary system (Ochiai et al, Carcinogenesis 2019), pancreas (Matsuura et al, Carcinogenesis 2020), stomach and female reproductive organs. Through these studies, we showed that even a major mutation is not tumorigenic in itself, but could be rather declined unless other mutations were co-introduced, and that the subcutis of nude mice provides unique niche for positive selection and upgrading of transformed cells. In a subset of cases, however, we observed significantly promoted or mitigated tumorigenicity compared to the counterpart mouse models in vivo, suggesting the relevance of interactions between particular mutations and microenvironment as the critical determinant of tumorigenicity. By modifying the MBOC protocol, we newly established multiple patient-derived organoids from gynecological cancers (Maru et al, Gynecol Oncol 2019; Maru et al, Cancer Sci 2019), for which few studies had reported long-term culture (Maru and Hippo, Cells 2019). These efforts toward implementation of precision medicine will be also presented in this seminar.