Portal vein injection of colorectal cancer organoids to study the liver metastasis stroma

Hiroki Kobayashi, Krystyna A. Gieniec, Jia Q. Ng, Jarrad Goyne, Tamsin R.M. Lannagan, Elaine M. Thomas, Georgette Radford, Tongtong Wang, Nobumi Suzuki, Mari Ichinose, Josephine A. Wright, Laura Vrbanac, Alastair D. Burt, Masahide Takahashi, Atsushi Enomoto, Daniel L. Worthley, Susan L. Woods

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere62630
JournalJournal of Visualized Experiments
Volume2021
Issue number175
DOIs
Publication statusPublished - 09-2021

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Chemical Engineering
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

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