Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer
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 constitu...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1223915/full |
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| author | Yurong Song Travis D. Kerr Chelsea Sanders Lisheng Dai Shaneen S. Baxter Brandon Somerville Ryan N. Baugher Stephanie D. Mellott Todd B. Young Heidi E. Lawhorn Teri M. Plona Bingfang Xu Lei Wei Qiang Hu Song Liu Alan Hutson Baktiar Karim Sandra Burkett Simone Difilippantonio Ligia Pinto Johannes Gebert Matthias Kloor Steven M. Lipkin Shizuko Sei Robert H. Shoemaker |
| author_facet | Yurong Song Travis D. Kerr Chelsea Sanders Lisheng Dai Shaneen S. Baxter Brandon Somerville Ryan N. Baugher Stephanie D. Mellott Todd B. Young Heidi E. Lawhorn Teri M. Plona Bingfang Xu Lei Wei Qiang Hu Song Liu Alan Hutson Baktiar Karim Sandra Burkett Simone Difilippantonio Ligia Pinto Johannes Gebert Matthias Kloor Steven M. Lipkin Shizuko Sei Robert H. Shoemaker |
| author_sort | Yurong Song |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T01:47:01Z |
| format | Article |
| id | doaj.art-0d2e5d6b71eb4b909e5643961c4ff61e |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-12T01:47:01Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-0d2e5d6b71eb4b909e5643961c4ff61e2023-09-08T20:41:35ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-09-011310.3389/fonc.2023.12239151223915Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancerYurong Song0Travis D. Kerr1Chelsea Sanders2Lisheng Dai3Shaneen S. Baxter4Brandon Somerville5Ryan N. Baugher6Stephanie D. Mellott7Todd B. Young8Heidi E. Lawhorn9Teri M. Plona10Bingfang Xu11Lei Wei12Qiang Hu13Song Liu14Alan Hutson15Baktiar Karim16Sandra Burkett17Simone Difilippantonio18Ligia Pinto19Johannes Gebert20Matthias Kloor21Steven M. Lipkin22Shizuko Sei23Robert H. Shoemaker24Frederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Clinical Laboratory Improvement Amendments (CLIA) Molecular Diagnostics Laboratory, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Genomics Laboratory, Frederick, MD, United StatesDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesDepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United StatesMolecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, United StatesMolecular Cytogenetics Core Facility, National Cancer Institute, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Laboratory Animal Sciences Program, Frederick, MD, United StatesFrederick National Laboratory for Cancer Research, Vaccine, Immunity, and Cancer Directorate, Frederick, MD, United StatesDepartment of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, GermanyDepartment of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, GermanyDepartment of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, United States0Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United States0Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, United StatesBackgroundGenome 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1223915/fullmismatch repair deficiencyLynch syndromemicrosatellite instabilitychromosome instabilityMSH2organoid |
| spellingShingle | Yurong Song Travis D. Kerr Chelsea Sanders Lisheng Dai Shaneen S. Baxter Brandon Somerville Ryan N. Baugher Stephanie D. Mellott Todd B. Young Heidi E. Lawhorn Teri M. Plona Bingfang Xu Lei Wei Qiang Hu Song Liu Alan Hutson Baktiar Karim Sandra Burkett Simone Difilippantonio Ligia Pinto Johannes Gebert Matthias Kloor Steven M. Lipkin Shizuko Sei Robert H. Shoemaker Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer Frontiers in Oncology mismatch repair deficiency Lynch syndrome microsatellite instability chromosome instability MSH2 organoid |
| title | Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer |
| title_full | Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer |
| title_fullStr | Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer |
| title_full_unstemmed | Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer |
| title_short | Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer |
| title_sort | organoids and metastatic orthotopic mouse model for mismatch repair deficient colorectal cancer |
| topic | mismatch repair deficiency Lynch syndrome microsatellite instability chromosome instability MSH2 organoid |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1223915/full |
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