| Autor: |
Kobayashi H; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI); Department of Pathology, Nagoya University Graduate School of Medicine; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine., Gieniec KA; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Ng JQ; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Goyne J; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Lannagan TRM; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Thomas EM; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Radford G; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Wang T; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Suzuki N; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI); Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo., Ichinose M; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Wright JA; South Australian Health and Medical Research Institute (SAHMRI)., Vrbanac L; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI)., Burt AD; Translational and Clinical Research Institute, Newcastle University., Takahashi M; Department of Pathology, Nagoya University Graduate School of Medicine; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine; International Center for Cell and Gene Therapy, Fujita Health University., Enomoto A; Department of Pathology, Nagoya University Graduate School of Medicine., Worthley DL; South Australian Health and Medical Research Institute (SAHMRI); dan@colonoscopyclinic.com.au., Woods SL; Adelaide Medical School, University of Adelaide; South Australian Health and Medical Research Institute (SAHMRI); susan.woods@adelaide.edu.au. |
| Abstrakt: |
Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC. |
