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@ARTICLE{Song:286251,
      author       = {Y. Song and T. D. Kerr and C. Sanders and L. Dai and S. S.
                      Baxter and B. Somerville and R. N. Baugher and S. D. Mellott
                      and T. B. Young and H. E. Lawhorn and T. M. Plona and B. Xu
                      and L. Wei and Q. Hu and S. Liu and A. Hutson and B. Karim
                      and S. Burkett and S. Difilippantonio and L. Pinto and J.
                      Gebert and M. Kloor and S. M. Lipkin and S. Sei and R. H.
                      Shoemaker},
      title        = {{O}rganoids and metastatic orthotopic mouse model for
                      mismatch repair-deficient colorectal cancer.},
      journal      = {Frontiers in oncology},
      volume       = {13},
      issn         = {2234-943X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2023-02742},
      pages        = {1223915},
      year         = {2023},
      abstract     = {Genome 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.To 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.The 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.The
                      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.},
      keywords     = {Lynch syndrome (Other) / MSH2 (Other) / chromosome
                      instability (Other) / colorectal cancer (Other) /
                      microsatellite instability (Other) / mismatch repair
                      deficiency (Other) / mouse model (Other) / organoid (Other)},
      cin          = {F210},
      ddc          = {610},
      cid          = {I:(DE-He78)F210-20160331},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37746286},
      pmc          = {pmc:PMC10516605},
      doi          = {10.3389/fonc.2023.1223915},
      url          = {https://inrepo02.dkfz.de/record/286251},
}