Biology subjects

Leor, G.

Publications and source records attributed to Leor, G..

5 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↗

bioRxiv2025

Chromosome-arm 17p Loss Renders Breast Cancer Cells Vulnerable to AURKB Inhibition

Loss of chromosome-arm 17p (Del17p) is a genetic hallmark of breast cancer. While TP53 loss is an established driver of Del17p, the potential therapeutically-relevant cellular vulnerabilities of this common aneuploidy remain unexplored. Here, we first analyzed genomic and clinical data from breast cancer patients using METABRIC and TCGA datasets. Del17p was prevalent across molecular subtypes and correlated with higher tumor grade, advanced stage, and worse survival. Gene expression profiling revealed reduced expression and activity of the chromosome 17p-residing gene Aurora Kinase B (AURKB) in Del17p tumors and cell lines. Moreover, functional dependency screens across breast cancer cell lines identified increased sensitivity of Del17p cells to genetic inhibition of AURKB, which we validated using chemical inhibition in matched breast cancer cell lines. Next, we generated an isogenic model of CAL51 breast cancer cells with/without heterozygous AURKB loss in TP53-WT and TP53-null backgrounds, and confirmed that heterozygous loss of AURKB resulted in its reduced expression and in increased sensitivity to the AURKB inhibitor barasertib. Notably, p53 inactivation increased AURKB expression and reduced drug sensitivity, as previously reported, but AURKB heterozygous knockout reverted these phenotypes, revealing opposite effects of common modes of p53 inactivation (Del17p vs. point mutations). Mechanistically, the phenotypes associated with barasertib treatment - mitotic aberrations, cytokinesis failure, whole-genome doubling and apoptosis - were exacerbated in Del17p cells. Our findings therefore suggest Del17p as a potential biomarker for identifying breast cancer patients who may benefit from AURKB inhibition and highlight its potential as a therapeutic target in Del17p breast tumors. SignificanceBreast cancer tumors with loss of chromosome-arm 17p (Del17p) exhibit reduced AURKB expression and increased sensitivity to AURKB inhibition, suggesting Del17p as a biomarker for AURKB-targeted therapy.

cancer biology↗

bioRxiv2024

Chromosome 7 to the rescue: overcoming chromosome 10 loss in gliomas

The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair in human cancers, a phenomenon that has been investigated without resolution since the late 1980s. Expanding beyond previous gene-centric studies, we investigate the co-occurrence in a genome-wide manner taking an evolutionary perspective. First, by mining large tumor aneuploidy data, we predict that the more likely order is 10 loss followed by 7 gain. Second, by analyzing extensive genomic and transcriptomic data from both patients and cell lines, we find that this co-occurrence can be explained by functional rescue interactions that are highly enriched on 7, which can possibly compensate for any detrimental consequences arising from the loss of 10. Finally, by analyzing transcriptomic data from normal, non-cancerous, human brain tissues, we provide a plausible reason why this co-occurrence happens preferentially in cancers originating in certain regions of the brain.

cancer biology↗

bioRxiv2023

Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage

Aneuploidy is a hallmark of human cancer, yet the cellular mechanisms that allow cells to cope with aneuploidy-induced cellular stresses remain largely unknown. Such coping mechanisms may present cellular vulnerabilities that can be harnessed for targeting cancer cells. Here, we induced aneuploidy in non-transformed RPE1-hTERT cells and derived multiple stable clones with various degrees of chromosome imbalances. We performed an unbiased genomic profiling of 6 isogenic clones, using whole-exome and RNA sequencing. We then functionally interrogated their cellular dependency landscapes, using genome-wide CRISPR/Cas9 screens and large-scale drug screens. We found that aneuploid clones activated the DNA damage response (DDR), and were consequently more resistant to further DNA damage induction. Interestingly, aneuploid cells also exhibited elevated RAF/MEK/ERK pathway activity, and were more sensitive to several clinically-relevant drugs targeting this pathway, and in particular to genetic and chemical CRAF inhibition. CRAF activity was functionally linked to the resistance to DNA damage induction, as CRAF inhibition sensitized aneuploid cells to DNA damage-inducing chemotherapies. The association between aneuploidy, RAF/MEK/ERK signaling, and DDR was independent of p53. The increased activity and dependency of aneuploid cells on the RAF/MEK/ERK pathway was validated in another isogenic aneuploid system, and across hundreds of human cancer cell lines, confirming their relevance to human cancer. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a novel therapeutically-relevant cellular dependency of aneuploid cells.

cancer biology↗

bioRxiv2021

Whole-genome duplication shapes the aneuploidy landscape of human cancers

Aneuploidy - a hallmark of cancer - has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.

cancer biology↗