シンポジウム 1

Understanding of cancer heterogeneityand chemoresistance using patient-derived
spheroid models

Koji Okamoto
Division of Cancer Differentiation
National Cancer Center Research Institute

In order to devise an effective therapeutic strategy against refractory cancers, it is important[References]

to develop model systems which faithfully recapitulate in vivo tumors and serve as platforms to

1. Ohata H, Shiokawa D, Obata Y, Sato A, Sakai H, Fukami M, Hara W, Taniguchi H, Ono M, Nakagama H,validate efficacies for novel therapeutic agents. However, it has been reported that conventional
cell lines often fail to mimic clinical effectiveness against anti-tumor agents. We have developed
long-term spheroid culture system from clinical specimens of colon and ovarian cancer (ref. 3,5). The established spheroids seem to retain characteristics of the original tumors, as they canOkamoto K. NOX1-dependent mTORC1 activation via S100A9 oxidation in cancer stem-like cells leads
to colon cancer progression. Cell Reports in press.
2. Shiokawa D, Sato A, Ohata H, Mutoh M, Sekine S, Kato M, Shibata T, Nakagama H, Okamoto K. The
Induction of Selected Wnt Target Genes by Tcf1 Mediates Generation of Tumorigenic Colon StemCells. Cell Reports 19, 981-994, 2017

generate tumors that faithfully mimics histology of the original tumor after xenograft formation

3. Ishiguro T, Sato A, Ohata H, Ikarashi Y, Takahashi R, Ochiya T, Yoshida M, Tsuda H, Onda T, Kato T,

in immunodeficient mice. Hence these spheroids may serve as invaluable systems to investigate

Kasamatsu T, Enomoto T, Tanaka K, Nakagama H, Okamoto K. Establishment and characterization ofnature of cancer chemoresistance.
Using the established spheroids. several experiments are in progress to understandmalignant nature of these cancers. Because accumulating reports indicate that cancer cells arecomposed of heterologous populations with different chemosensitivity, we perform RNA-seq

an in vitro model of ovarian cancer stem-like cells with an enhanced proliferative capacity. Cancer Res .
76, 150-160, 2016
4. Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S,Inoue T, Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T. TNIK inhibition abrogates colorectal
cancer stemness. Nature Commun . 7, 12586, 2016

gene expression analyses of colon cancer xenograft at single-cell levels to understand biological

5. Ohata H, Ishiguro T, Aihara Y, Sato A, Sakai H, Sekine S, Taniguchi H, Akasu T, Fujita S, Nakagama H,features of the chemoresistant cells. Exposure to chemotherapeutic agents revealed that there

Okamoto K. Induction of the stem-like cell regulator CD44 by Rho kinase inhibition contributes to theexists chemoresistant slow-growing cancer cells in xenograft tumors. The precise nature of thechemoresistant cells are under investigation.
As another strategy to understand mechanism of chemoresistance, we combined

maintenance of colon cancer-initiating cells. Cancer Res . 72, 5101-5110, 2012
6. Okamoto K, Ishiguro T, Midorikawa Y, Ohata H, Izumiya M, Tsuchiya N, Sato A, Sakai H, Nakagama
H. miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver.

EMBO J . 31, 1752-1763, 2012transcriptome analyses and systematic investigation of chemoresistance in a panel of patientderived spheroids from ovarian cancer. We found that the spheroids showed a varied
effectiveness toward platinum-based compounds. Further investigation revealed that expressionof several glycolytic genes was associated with cisplatin chemoresistance.

Koji Okamoto, MD, PhD
Chief, National Cancer Center Research Institute
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Tokyo University, Faculty of Medicine, MD
Resident, Tokyo University Hospital
Post-doctoral fellow, Cold Spring Harbor Laboratory
PhD, Tokyo University, Graduate School of Medicine
Post-doctoral fellow, Columbia University
Section Head, National Cancer Center Research Institute, Radiobiology Division
Chief, National Cancer Center Research Institute, Division of Cancer
Differentiation

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