Onno Kranenburg is Professor Translational Tumor Biology at the University Medical Center Utrecht (UMCU) and heads the Lab Translational Oncology.

He is also a member of the daily board of the focus area Cancer at the UMCU, coordinator of the PhD education program Clinical and Translational Oncology, and chair of the Utrecht Platform for Organoid Technology (U-PORT).

U-PORT supports the application and further development of organoid technology. Organoids provide excellent model systems for studying all the hallmarks of cancer, including cancer metastasis.

Using colorectal cancer organoids, Kranenburg studies multiple aspects of CRC metastasis, including mechanisms of organ-specific dissemination, survival and outgrowth.

New insights in CRC metastasis biology are used to develop novel diagnostic tools and treatment strategies. These are tested in organoid-based mouse models and, ultimately, in clinical studies.

ABSTRACT

Title: Organoid-based models for metastatic Colorectal Cancer with high microsatellite instability 

Summary: Colorectal Cancers (CRC) with a deficient mismatch repair system (dMMR) are characterized by a high level of microsatellite instability (MSI-H) and a hyper-mutated genome. MSI-H is associated with a relatively good prognosis in primary CRC, but with poor prognosis in metastatic CRC (mCRC).

The immunogenic nature of MSI-H mCRC tumors underlies their unique responsiveness to immune-checkpoint inhibitors (ICIs), but response rates are highly variable. Model systems for further pre-clinical optimization of the treatment of MSI-H mCRC are currently lacking.

We describe the establishment of organoids from MSI-H mCRC tumors and organoid-initiated metastasis models, using immune-deficient and Human Immune System (HIS) mice.

The results demonstrate that organoids from MSI-H mCRC can be used for building spontaneous metastasis models in mice involving all relevant distant sites, and in the context of a human immune system. This allows for evaluation of ICI therapies and for further improving ICI-based therapeutic strategies.