Masanobu OSHIMA

Polyclonal metastasis of colorectal cancer

Nano Life Science Institute (WPI-NanoLSI),
Cancer Research Institute, Kanazawa University, Japan

Masanobu OSHIMA
Nano Life Science Institute (WPI-NanoLSI), Cancer Research InstituteKanazawa University, Japan

Contact : oshimam [at sign] staff.kanazawa-u.ac.jp
Please replace [at sign] with @.

Colorectal cancer (CRC) is a leading cause of cancer-related death globally, and the majority of cancer-related deaths
are caused by metastasis. It is therefore important to predict metastatic ability of the primary cancers to establish aResearch Interests
Mouse genetics, organoid, microscopy imaging, microenvironment, metastasis

colorectal cancer, and comprehensive genome research has identified driver genes that are frequently mutated in CRC.
Using genetic mouse models, we have constructed mouse models and established intestinal tumor-derived organoids
carrying various combinations of driver mutations, Apc (A), Kras (K), Tgfbr2 (T), Trp53 (P), and Fbxw7 (F).
Comprehensive phenotype analyses revealed that AT and AP mutation combinations cause submucosal invasion, AKT

Education
1982 - 1986
1986 - 1988

clinical strategy. The accumulation of driver mutations is responsible for development and malignant progression ofand AKP combinations induce advanced malignant phenotype like epithelial-mesenchymal transition (EMT), and AKTP
Faculty of Veterinary Medicine, Hokkaido University
Hokkaido University Graduate School of Veterinary Medicine (MS)and AKTPF acquire highly metastatic ability from the spleen to liver [1-3], which is consistent with the establishedconcept of multistep tumorigenesis based on Darwin evolution. However, a unique concept for metastasis, polyclonal
metastasis, has recently been proposed. We therefore examined the mechanism of polyclonal metastasis by labeled
the intestinal tumor-derived organoids with Venus and tdTomato. When non-metastatic (Non-M) cells are transplanted

Professional Career

into the spleen with malignant metastatic (MM) cells, they

1988 - 1991

Staff Scientist, Chugai Pharmaceutical Co. Ltd.

cells, but not Non-M cells, induce niche generation

1992 - 1997

Staff Scientist, Banyu Tsukuba Research Institute (Merck)

1997 - 1999
2000 - 2005

Research Associate, Merck Research Laboratories, USA

expressing cells promotes the colonization of Non-M cells.

Associate Professor, Kyoto University Graduate School of Medicine

metastasize via the polyclonal mechanism using the2005 - present2017 - present

Professor, Cancer Research Institute, Kanazawa University

microenvironment that is generated by malignant cells.

form chimeric metastatic foci in the liver. Importantly, MMsurrounding disseminated tumor clusters, and suchmicroenvironment consisting of macrophages and αSMAT h e s e re s u l t s i n d i c a t e t h a t n o n - m e t a s t a t i c c e l l s c a n

Professor, Nano Life Science Institute (WPI-NanoLSI), Kanazawa UniversityAKTP organoids

AKTP and AP chimeric spheroids
for spleen transplantation

Scientific Activities
1992 - 2005

Mouse genetics studies for chemoprevention of intestinal tumorigenesis

2005 - present

Mouse genetics and organoid research for gastrointestinal cancer malignant progression

References[ 1 ] Oshima H, Nakayama M, Han TS, Naoi K, Ju X, Maeda Y, Robine S, Tsuchiya K, Sato T, Taketo MM, and Oshima M.

Honors
2012
2013
2015
2020

Suppressing TGF-β signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause
invasive intestinal cancer. Cancer Res, 75: 754-765, 2015.
JCA-Mauverynay Award, Japanese Cancer Association
Achievement Commendation of Kanazawa University, Kanazawa University
The Commendation for Science and Technology, MEXT
Ishikawa Television Award, Ishikawa TV Broadcasting Co. LtdPublications[ 2 ] Nakayama M, Sakai E, Echizen K, Yamada Y, Oshima H, Han TS, Ohki R, Fujii F, Ochiai A, Robine S, Voon DC,Tanaka T, Taketo MM, and Oshima M. Intestinal cancer progression by mutant p53 through the acquisition ofinvasiveness associated with complex glandular formation. Oncogene, 36: 5885-5896, 2017.
[ 3 ] Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI, Mimori K, Suzuki Y, Hong CP,Ock CY, Kim SJ, and Oshima M. Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer. Cancer Res, 78: 1334-1346, 2018.

Nakayama M, Hong CP, Oshima H, Sakai E, Kim SJ, and Oshima M. Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition

1. of survival and tumor-initiating properties. Nat Commun, 11: 2333. 2020.

Takeda H, Kataoka S, Nakayama M, Ali MAE, Oshima H, Yamamoto D, Park JW, Takegami Y, An T, Jenkins NA, Copeland NG, and Oshima M.

2. CRISPR-Cas9 mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes. Proc Natl Acad
Sci USA, 116: 15635-15644, 2019.

Oshima H, Kok SY, Nakayama M, Murakami K, Voon DC, Kimura T, and Oshima M. Stat3 is indispensable for damage-induced crypt regeneration but

3. not for Wnt-driven intestinal tumorigenesis. FASEB J, 2019.
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