Patient-Derived Explants of Colorectal Cancer: Histopathological and Molecular Analysis of Long-Term Cultures

Simple Summary Colorectal cancer is the third most common cancer type among men and women. Prescription of medical treatments for cancer often relies on a process of trial and potential error, more recently guided by patient stratification based on biomarkers. Nonetheless, available biomarkers do not accurately predict patient response and there is a need for predictive and translational models to provide proper clinical information on treatment guidance. Herein, we developed an ex vivo model of colorectal cancer, using fresh tumour samples to establish explant cultures, taking advantage of agitation-based culture systems. We performed a thorough characterisation over one month in culture and observed preservation of original tumour genetic features and partial preservation of architecture and non-malignant cells that compose the tumour microenvironment. Our findings highlight the importance of detailed model characterisation and support the applicability of our model in pre- and co-clinical settings. Colorectal cancer (CRC) is one of the most common cancers worldwide. Although short-term cultures of tumour sections and xenotransplants have been used to determine drug efficacy, the results frequently fail to confer clinically useful information. Biomarker discovery has changed the paradigm for advanced CRC, though the presence of a biomarker does not necessarily translate into therapeutic success. To improve clinical outcomes, translational models predictive of drug response are needed. We describe a simple method for the fast establishment of CRC patient-derived explant (CRC-PDE) cultures from different carcinogenesis pathways, employing agitation-based platforms. A total of 26 CRC-PDE were established and a subset was evaluated for viability (n = 23), morphology and genetic key alterations (n = 21). CRC-PDE retained partial tumor glandular architecture and microenvironment features were partially lost over 4 weeks of culture. Key proteins (p53 and Mismatch repair) and oncogenic driver mutations of the original tumours were sustained throughout the culture. Drug challenge (n = 5) revealed differential drug response from distinct CRC-PDE cases. These findings suggest an adequate representation of the original tumour and highlight the importance of detailed model characterisation. The preservation of key aspects of the CRC microenvironment and genetics supports CRC-PDE potential applicability in pre- and co-clinical settings, as long as temporal dynamics are considered.

Automated summary

The study outlines the development of a colorectal cancer ex vivo model using fresh tumor samples, highlighting the preservation of original tumor genetic features and partial retention of architecture and non-malignant cells in culture. The model shows promise for use in pre- and co-clinical settings.