Raz, L. | Search bioRxiv

bioRxiv2025

Pan-cancer analysis reveals genomic fidelity and evolution of patient-derived organoids

BackgroundPatient-derived organoids (PDOs) are gaining recognition as a promising ex vivo model for cancer research, offering advantages over traditional 2D cell lines by better recapitulating tumor biology. ResultsIn this study, we assess the genomic stability and evolution of PDOs by analyzing copy-number alterations (CNAs) in 300 PDO samples across 16 cancer types. These results are compared with data from previously analyzed patient-derived xenografts (PDXs). We observe that PDOs exhibit genomic evolution over passaging, with an increasing divergence from the original tumor genome over time. Importantly, across cancer types, PDOs maintain higher genomic fidelity and are more genetically similar to their tumors of origin than PDX models. Moreover, PDOs show greater genomic stability during culture passaging compared to PDXs. ConclusionsThese findings position PDOs as a reliable and representative model for cancer research, while highlighting the need to carefully track their genomic evolution in culture.

cancer biology↗

bioRxiv2023

CDC20 determines the sensitivity to spindle assembly checkpoint (SAC) inhibitors

Spindle assembly checkpoint (SAC) inhibitors are a recently developed class of drugs that perturb the regulation of chromosome segregation during division, induce chromosomal instability (CIN), and eventually lead to cell death. While they are currently in clinical trials for solid cancers, biomarkers to predict the response to SAC inhibitors are still lacking. We recently reported that aneuploid cancer cells are preferentially sensitive to SAC inhibition. Here, we investigated the molecular determinants of the response to SAC inhibition that underlies the differential sensitivity of aneuploid cells to these drugs. We found that this response was largely driven by the expression of CDC20, a main activator of the anaphase-promoting complex (APC/C), rather than by APC/C itself. Mechanistically, we discovered that CDC20 depletion prolonged metaphase duration, diminished mitotic errors, and reduced sensitivity to SAC inhibition. Aneuploid cells expressed high levels of CDC20 and experienced shorter metaphases and multiple mitotic errors, resulting in increased long-term sensitivity to SAC inhibition. Our findings propose high CDC20 expression as a favorable biomarker for SAC inhibition therapy and as an aneuploidy-induced therapeutic vulnerability.

cancer biology↗