慶應義塾研究者情報データベース

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• 2005年04月

  -

  2011年03月

  慶應義塾大学, 医学部

  大学, 卒業

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• An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

  Kawasaki K., Toshimitsu K., Matano M., Fujita M., Fujii M., Togasaki K., Ebisudani T., Shimokawa M., Takano A., Takahashi S., Ohta Y., Nanki K., Igarashi R., Ishimaru K., Ishida H., Sukawa Y., Sugimoto S., Saito Y., Maejima K., Sasagawa S., Lee H., Kim H.G., Ha K., Hamamoto J., Fukunaga K., Maekawa A., Tanabe M., Ishihara S., Hamamoto Y., Yasuda H., Sekine S., Kudo A., Kitagawa Y., Kanai T., Nakagawa H., Sato T.

  Cell （Cell）  183 （ 5 ） 1420 - 1435.e21 2020年11月

  ISSN  00928674

  　概要を見る

  © 2020 Elsevier Inc. Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes. Gastroenteropancreatic neuroendocrine neoplasms are a rare but lethal cancer with a scarcity of clinically relevant models. Kawasaki et al. establish and characterize 25 organoid lines to identify molecular subtypes with genotype-phenotype mapping.

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• Chromosome Engineering of Human Colon-Derived Organoids to Develop a Model of Traditional Serrated Adenoma

  Kawasaki K., Fujii M., Sugimoto S., Ishikawa K., Matano M., Ohta Y., Toshimitsu K., Takahashi S., Hosoe N., Sekine S., Kanai T., Sato T.

  Gastroenterology （Gastroenterology）  158 （ 3 ） 638 - 651.e8 2020年02月

  ISSN  00165085

  　概要を見る

  © 2020 AGA Institute Background & Aims: Traditional serrated adenomas (TSAs) are rare colorectal polyps with unique histologic features. Fusions in R-spondin genes have been found in TSAs, but it is not clear whether these are sufficient for TSA development, due to the lack of a chromosome engineering platform for human tissues. We studied the effects of fusions in R-spondin genes and other genetic alterations found in TSA using CRISPR-Cas9–mediated chromosome and genetic modification of human colonic organoids. Methods: We introduced chromosome rearrangements that involve R-spondin genes into human colonic organoids, with or without disruption of TP53, using CRISPR-Cas9 (chromosome-engineered organoids). We then knocked a mutation into BRAF encoding the V600E substitution and overexpressed the GREM1 transgene; the organoids were transplanted into colons of NOG mice and growth of xenograft tumors was measured. Colon tissues were collected and analyzed by immunohistochemistry or in situ hybridization. We also established 2 patient-derived TSA organoid lines and characterized their genetic features and phenotypes. We inserted a bicistronic cassette expressing a dimerizer-inducible suicide gene and fluorescent marker downstream of the LGR5 gene in the chromosome-engineered organoids; addition of the dimerizer eradicates LGR5+ cells. Some tumor-bearing mice were given intraperitoneal injections of the dimerizer to remove LGR5-expressing cells. Results: Chromosome engineering of organoids required disruption of TP53 or culture in medium containing IGF1 and FGF2. In colons of mice, organoids that expressed BRAFV600E and fusions in R-spondin genes formed flat serrated lesions. Patient-derived TSA organoids grew independent of exogenous R-spondin, and 1 line grew independent of Noggin. Organoids that overexpressed GREM1, in addition to BRAFV600E and fusions in R-spondin genes, formed polypoid tumors in mice that had histologic features similar to TSAs. Xenograft tumors persisted after loss of LGR5-expressing cells. Conclusions: We demonstrated efficient chromosomal engineering of human normal colon organoids. We introduced genetic and chromosome alterations into human colon organoids found in human TSAs; tumors grown from these organoids in mice had histopathology features of TSAs. This model might be used to study progression of human colorectal tumors with RSPO fusion gene and GREM1 overexpression.

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• Somatic inflammatory gene mutations in human ulcerative colitis epithelium

  Nanki K., Fujii M., Shimokawa M., Matano M., Nishikori S., Date S., Takano A., Toshimitsu K., Ohta Y., Takahashi S., Sugimoto S., Ishimaru K., Kawasaki K., Nagai Y., Ishii R., Yoshida K., Sasaki N., Hibi T., Ishihara S., Kanai T., Sato T.

  Nature （Nature）  577 （ 7789 ） 254 - 259 2020年01月

  ISSN  00280836

  　概要を見る

  © 2019, The Author(s), under exclusive licence to Springer Nature Limited. With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1–7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling—including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8–11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

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• Multiple immune-related adverse events and anti-tumor efficacy: Real-world data on various solid tumors

  Shimozaki K., Sukawa Y., Beppu N., Kurihara I., Suzuki S., Mizuno R., Funakoshi T., Ikemura S., Tsugaru K., Togasaki K., Kawasaki K., Hirata K., Hayashi H., Hamamoto Y., Takaishi H., Kanai T.

  Cancer Management and Research （Cancer Management and Research）  12   4585 - 4593 2020年

  　概要を見る

  © 2020 Shimozaki et al. Purpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. Patients and Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33–0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346–0.647; P < 0.0001). Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

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• Post-progression survival following second-line chemotherapy in patients with advanced pancreatic cancer previously treated with gemcitabine: a meta-analysis

  Kasuga A., Hamamoto Y., Takeuchi A., Okano N., Togasaki K., Aoki Y., Suzuki T., Kawasaki K., Hirata K., Sukawa Y., Kanai T., Takaishi H.

  Investigational New Drugs （Investigational New Drugs）  36 （ 5 ） 939 - 948 2018年10月

  ISSN  01676997

  　概要を見る

  © 2018, Springer Science+Business Media, LLC, part of Springer Nature. Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. We evaluated relationships between OS and PFS, PPS, and other variables. Results Totally, 17 RCTs with 3253 patients were identified. Median OS was strongly and moderately associated with median PPS and PFS, respectively (r = 0.913; p < 0.001 and 0.780; p < 0.001, respectively). The proportion of patients with good performance status was significantly associated with both PPS and PFS (r = 0.574, p < 0.001 and 0.492, p < 0.001, respectively). The induction rate of subsequent chemotherapy was related to the duration of PPS and OS (r = 0.640, p < 0.001 and 0.647, p < 0.001, respectively). Median PPS and OS were significantly longer in recent trials than those in older trials (3.55 versus 2.78 months, p < 0.001 and 6.29 versus 5.02 months, p < 0.001). Conclusions Median PPS was strongly correlated with median OS. Given the recently increased opportunity for subsequent chemotherapy and supportive care, PPS may serve as an important element to clarify problems in this setting.

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