title: A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis.
abstract: Colorectal tumor is a heterogeneous disease, with varying clinical presentation and prognosis in patients. To establish a platform encompassing this diversity, we generated 55 colorectal tumor organoid lines from a range of histological subtypes and clinical stages, including rare subtypes. Each line was defined by gene expression signatures and optimized for organoid culture according to niche factor requirements. In vitro and in xenografts, the organoids reproduced the histopathological grade and differentiation capacity of their parental tumors. Notably, we found that niche-independent growth is predominantly associated with the adenoma-carcinoma transition reflecting accumulation of multiple mutations. For matched pairs of primary and metastatic organoids, which had similar genetic profiles and niche factor requirements, the metastasis-derived organoids exhibited higher metastatic capacity. These observations underscore the importance of genotype-phenotype analyses at a single-patient level and the value of our resource to provide insights into colorectal tumorigenesis and patient-centered therapeutic development.
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Surgical Oncology, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimokawa
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan; Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga 520-0106, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Date
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Takano
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Matano
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Nanki
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Toshimitsu
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakazato
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Division for Research and Development of Minor Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Uraoka
authors.affiliation: Department of Surgical Oncology, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.affiliation: Department of Gastroenterology, Cancer Center, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: t.sato@keio.jp.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D009940:Organoids / Q000378:metabolism / Q000473:pathology*; D055153:Stem Cell Niche / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D004815:Epidermal Growth Factor