New advances in the use of patient-derived organoids and mouse models for assessing heterogeneity among metastatic colorectal cancers.

Abstract

Metastatic colorectal cancers (mCRCs) exhibit substantial heterogeneity at the genetic, transcriptomic, histological, and microenvironmental levels, which contributes to therapeutic resistance and variable clinical outcomes. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) have emerged as powerful platforms for modeling this complex disease. PDOs faithfully recapitulate tumor architecture, molecular features, and heterogeneity, enabling high-throughput drug screening and personalized treatment response prediction. In addition, PDX models maintain tumor-stroma interactionsand accurately reflect histological and pharmacological phenotypes, supporting studies on treatment response and resistance mechanisms. Recent advances indicate that these models capture intratumoral, intertumoral, and interpatient variability; reveal patterns and mechanisms of drug sensitivity heterogeneity; and can be used to predict chemotherapy efficacy. However, limitations remain for both model types. Innovations such as humanized PDX mouse models and immune‒organoid coculture systems are being developed to overcome these barriers. This review summarizes the latest progress in PDO and PDX applications in research on mCRC heterogeneity, highlights their role in dissecting tumor heterogeneity, and discusses future directions for integrating these models into precision oncology.