Capturing colorectal cancer inter‐tumor heterogeneity in patient‐derived xenograft (PDX) models

• Published in: International journal of cancer Vol. 144; no. 2; pp. 366 - 371
• Main Authors: Prasetyanti, Pramudita R., Hooff, Sander R., Herwaarden, Tessa, Vries, Nathalie, Kalloe, Kieshen, Rodermond, Hans, Leersum, Ronald, Jong, Joan H., Franitza, Marek, Nürnberg, Peter, Todaro, Matilde, Stassi, Giorgio, Medema, Jan Paul
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.01.2019; Wiley Subscription Services, Inc
• Subjects: Cancer; Cell proliferation; CMS; Colorectal cancer; Colorectal carcinoma; Medical research; PDX; Tumor Markers and Signatures; tumor subtype; xenograft; Xenografts; CMS; colorectal cancer; cell proliferation; xenograft; tumor subtype; PDX
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.31767

Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, to provide a robust preclinical platform, PDXs need to accommodate the tumor heterogeneity that is observed in patients. Colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features. Surprisingly, using a set of CRC patients, we revealed the partial representation of tumor heterogeneity in PDX models. The epithelial subtypes, the largest subgroups of CRC subtype, were very ineffective in establishing PDXs, indicating the need for further optimization to develop an effective personalized therapeutic approach to CRC. Moreover, we showed that tumor cell proliferation was associated with successful PDX establishment and able to distinguish patient with poor clinical outcomes within CMS2 group. What's new? Patient‐derived xenograft (PDX) models have become an important asset in translational cancer research. However, colorectal cancer (CRC) can be stratified into four consensus molecular subtypes (CMS) with distinct biological and clinical features, and to what extent the existing CRC PDX collection represents the inter‐patient heterogeneity remains an open question. This study identifies a subtype‐specific bias in the establishment of PDXs from CRC patients, leaving the major subtype CMS2 strongly underrepresented. Additionally, the findings suggest that further classification within CMS can be achieved. For CMS2, the proliferation‐related marker Ki67 may thus help refine patient classification, estimate prognosis, and guide treatment decisions.