XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients

Abstract

The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids. Multidimensional omics analyses indicate that tumoroids retain extensive molecular fidelity with parental PDXs. A tumoroid-based trial with the anti-EGFR antibody cetuximab reveals variable sensitivities that are consistent with clinical response biomarkers, mirror tumor growth changes in matched PDXs, and recapitulate EGFR genetic deletion outcomes. Inhibition of adaptive signals upregulated by EGFR blockade increases the magnitude of cetuximab response. These findings illustrate the potential of large living biobanks, providing avenues for molecularly informed preclinical research in oncology.

Improvement of preclinical models is critical for ensuring effective treatment discovery for colorectal cancer. Here, the authors develop a platform of 128 PDX models from metastatic colorectal cancer with matched tumouroid cultures, and use these to demonstrate molecular concordance between PDX-tumouroid pairs, cetuximab sensitivity heterogeneity, and adaptive upregulation of druggable targets under cetuximab pressure.