title: Suppression of intestinal tumors by targeting the mitotic spindle of intestinal stem cells.
abstract: Human colorectal cancer is often initiated by the aberrant activation of Wnt signaling, notably following adenomatous polyposis coli (Apc) inactivation. Recent studies identified adult intestinal stem cells (ISCs) and demonstrated their role as the cells of origin for intestinal tumors. However, the early consequences of aberrant Wnt signaling activation remain to be fully elucidated. Here, using organoid cultures established from conditional knockout mice and in vitro gene ablation, we show that Apc inactivation led to aberrant ISC proliferation and the expansion of the crypt domain. This system was used to evaluate the potential of a cancer-related spindle protein, Tacc3, as a target of cancer therapy, as its disruption led to the suppression of tumor formation in an animal model of intestinal tumors. We found that Tacc3 is required for the proper mitosis of Apc-deficient ISCs, and its disruption significantly attenuated the expansion of the crypt domain. In vivo analysis of corresponding mutant mice demonstrated that Tacc3 disruption led to a significant decrease in tumor number and prolonged survival. These observations demonstrated that Tacc3 is a potential chemotherapeutic target for intestinal tumors by perturbing the aberrant cell proliferation of Apc-deficient ISCs and provides an opportunity for the development of novel cancer prevention and treatment.
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yao
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Oyanagi
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Natsume
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Kusama
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nagayama
authors.affiliation: Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.|Director's Room, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Noda
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005326:Fetal Proteins / Q000235:genetics; D015870:Gene Expression; D055786:Gene Knockout Techniques; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009940:Organoids; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D016019:Survival Analysis; D015533:Transcriptional Activation; D047368:Tumor Burden; D060449:Wnt Signaling Pathway
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; D005326:Fetal Proteins; C493597:Lgr5 protein, mouse; D008869:Microtubule-Associated Proteins; D043562:Receptors, G-Protein-Coupled; C418485:TACC3 protein, mouse