Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

Frontiers in Oncology

Oncology

Shizuko Sei¹  Robert H. Shoemaker¹  Johannes Gebert²  Matthias Kloor²  Lei Wei³  Alan Hutson³  Song Liu³  Qiang Hu³  Steven M. Lipkin⁴  Ryan N. Baugher⁵  Todd B. Young⁵  Heidi E. Lawhorn⁵  Stephanie D. Mellott⁵  Teri M. Plona⁵  Bingfang Xu⁶  Simone Difilippantonio⁷  Chelsea Sanders⁷  Brandon Somerville⁸  Lisheng Dai⁸  Travis D. Kerr⁸  Shaneen S. Baxter⁸  Yurong Song⁸  Ligia Pinto⁸  Sandra Burkett⁹  Baktiar Karim^1,10 

[1] Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United States;Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany;Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States;Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, United States;Frederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United States;Frederick National Laboratory for Cancer Research, Genomics Laboratory, Frederick, MD, United States;Frederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United States;Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United States;Molecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, United States;Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United States;

关键词: mismatch repair deficiency;    Lynch syndrome;    microsatellite instability;    chromosome instability;    MSH2;    organoid;    mouse model;    colorectal cancer;   

DOI  :  10.3389/fonc.2023.1223915

 received in 2023-05-18, accepted in 2023-08-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundGenome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.MethodsTo better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.ResultsThe organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.ConclusionsThe established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.

【 授权许可】

Unknown   
Copyright © 2023 Song, Kerr, Sanders, Dai, Baxter, Somerville, Baugher, Mellott, Young, Lawhorn, Plona, Xu, Wei, Hu, Liu, Hutson, Karim, Burkett, Difilippantonio, Pinto, Gebert, Kloor, Lipkin, Sei and Shoemaker