Biology subjects

Ben-Yishay, T.

Publications and source records attributed to Ben-Yishay, T..

3 recordsLinked to original sources

bioRxiv2026

Mapping chromothripsis across human cancer cell lines reveals genome evolution and therapeutic vulnerabilities

Chromothripsis is a catastrophic chromosomal rearrangement found in ~40% of primary tumors, yet its landscape in cancer cell lines (CCLs) remains uncharacterized. To address this gap, we developed a pipeline to detect chromothripsis-like events from copy-number data alone, and mapped their occurrence across 1,646 human CCLs. Chromothripsis patterns were broadly conserved between primary tumors and CCLs, but CCLs displayed some distinct features and a significantly higher prevalence of chromothripsis. Chromothripsis continued to emerge during culture propagation, likely contributing to its increased prevalence in CCLs. Integrating genomic and functional data revealed selective vulnerabilities: chromothriptic cells were resistant to DNA damage-inducing agents but highly sensitive to histone deacetylase inhibitors (HDACi). Using isogenic models, we validated that HDACi could synergistically sensitize chromothriptic cells to DNA damage-inducing agents. Our study establishes the first comprehensive resource of chromothripsis in CCLs and reveals functional consequences and therapeutic vulnerabilities of chromothripsis-positive cancers.

cancer biology↗

bioRxiv2026

Chromosomal instability and chromosome 17p loss drive convergentNDE1 synthetic lethality in metastatic cancer cells

Recent studies have identified recurrent features of metastatic cancer cells such as their increased chromosomal instability (CIN) and frequent loss of the short arm of chromosome 17 (Chr17p). However, it remains unclear whether these features induce synthetic lethal vulnerabilities that can be used to specifically target metastatic disease. Using whole-genome CRISPR/Cas9 loss-of-function screens performed in matched primary and CIN-high brain-metastatic tumor models, we discovered that brain-metastatic cells exhibit increased sensitivity to the loss of diverse regulators of chromosome segregation. Knockout of one such regulator, NDE1, selectively inhibited the growth of brain-metastatic models in vitro and in vivo, an effect driven by the loss of STAG2 and consequent induction of CIN. Surprisingly, dependence on NDE1 was also highly correlated with loss of Chr17p across hundreds of cancer cell lines in DepMap, the result of losing the NDE1 paralog NDEL1, which resides at this locus. CIN and Chr17p loss are thus independently sufficient to drive NDE1 dependence in brain-metastatic cells, and the presence of both features increases NDE1 dependence additively. These findings demonstrate that metastasis evolution endows cancer cells with specific vulnerabilities, including one that is driven by two recurrently altered molecular features of metastatic disease.

cancer biology↗

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↗