Kuniaki Sato1,2, Atsushi Niida3, Takaaki Masuda1, Dai Shimizu1, Taro Tobo4, Yousuke Kuroda1, Hidetoshi Eguchi1, Takashi Nakagawa2, Yutaka Suzuki5, Koshi Mimori6. 1. Department of Surgery, Kyushu University Beppu Hospital, Oita, Japan. 2. Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 3. Division of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 4. Department of Clinical Laboratory Medicine and Pathology, Kyushu University Beppu Hospital, Oita, Japan. 5. Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan. 6. Department of Surgery, Kyushu University Beppu Hospital, Oita, Japan kmimori@beppu.kyushu-u.ac.jp.
Abstract
BACKGROUND: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking. MATERIALS AND METHODS: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses. RESULTS: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA. CONCLUSION: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH. Copyright
BACKGROUND: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking. MATERIALS AND METHODS: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses. RESULTS: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA. CONCLUSION: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH. Copyright
Authors: Hendrik J Kuiken; Sabin Dhakal; Laura M Selfors; Chandler M Friend; Tian Zhang; Maurizio Callari; Ron C J Schackmann; G Kenneth Gray; Jett Crowdis; Hyo-Eun C Bhang; Timour Baslan; Frank Stegmeier; Steven P Gygi; Carlos Caldas; Joan S Brugge Journal: Oncogene Date: 2021-10-26 Impact factor: 9.867