Biology subjects

Saad, R.

Publications and source records attributed to Saad, R..

6 recordsLinked to original sources

bioRxiv2026

Pan-cancer analysis of single-cell RNA sequencing data from 304 human tumors sheds light on the aneuploidy paradox

Aneuploidy poses a central paradox in cancer biology: it impairs cellular fitness in normal cells but drives cancer progression. To resolve this, we analyzed single cell transcriptomes from >665,000 cells - including [~]288,000 malignant cells - across 304 tumors and 15 cancer types. Integrating transcriptomics with inferred aneuploidy profiles, we characterized cell-intrinsic programs and interactions with the tumor microenvironment. Unexpectedly, highly aneuploid single cells exhibited reduced proliferation and metabolism, contrasting sharply with tumor-bulk profiles. We show this divergence is driven by karyotypic heterogeneity: in highly heterogeneous tumors, aneuploid cells display signatures of acute stress and negative selection. Conversely, in clonally aneuploid tumors, these detrimental signatures are lost and replaced by signatures of increased proliferation and enhanced metabolism, reflecting adaptation. Additionally, we identified consistent transcriptional programs driven by recurrent chromosome-arm alterations across both single cells and bulk tumors. These findings illuminate the selective forces shaping tumor evolution and the aneuploidy paradox. Statement Of SignificanceBy jointly evaluating gene expression and aneuploidy at single-cell resolution, we demonstrate that karyotypic heterogeneity underlies the transcriptional impact of aneuploidy, reveal distinct cellular responses to emerging versus stable states, and identify recurrent chromosomal alterations that drive conserved transcriptional programs. Our findings capture the dynamics of aneuploidy evolution in human tumors, providing novel insights into the aneuploidy paradox.

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↗

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↗

bioRxiv2025

Theobromine is Associated with Slower Epigenetic Ageing

Theobromine, a commonly consumed dietary alkaloid derived from cocoa, has been linked to extended lifespan in model organisms and to health benefits in humans. We examined associations between circulating theobromine intake, measured using serum metabolomics, and blood-based epigenetic markers of biological ageing in two European human population-based cohorts. Serum theobromine levels were significantly associated with reduced epigenetic age acceleration, as measured by GrimAge (p<2e-7) and DNAmTL (p<0.001) in over 500 individuals from the TwinsUK cohort, and both signals replicated in 1,160 individuals from the KORA cohort (p = 7.2e-08 and p = 0.007, respectively). Sensitivity analyses including covariates of other cocoa and coffee metabolites suggest that the effect is specific to theobromine. Our findings indicate that the reported beneficial links between theobromine intake on health and ageing extend to the molecular epigenetic level in humans.

genetics↗

bioRxiv2025

Cell and nuclear size are associated with chromosomal instability and tumorigenicity in cancer cells that undergo whole genome doubling

Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, the effects of non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, on tetraploid (4N) cancer cell physiology are less understood. Here, we show that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. We find that small size is associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD. Statement of SignificanceWe report that WGD generates tetraploid cancer cells that vary in size, with larger cells displaying high chromosomal instability and smaller cells exhibiting high fitness and tumorigenicity. Furthermore, WGD status and cancer cell nuclear size in human tumors correlated with patient survival, demonstrating the clinical relevance of this association.

cancer biology↗

bioRxiv2025

Integrating gene expression, mutation and copy number data to identify driver genes of recurrent chromosome-arm losses

Aneuploidy is a hallmark of cancer, yet the specific genes driving recurrent chromosome-arm losses remain largely unknown. Here, we present a systematic framework integrating gene expression, mutation, and copy number data to identify candidate driver genes of cancer type-specific recurrent chromosome-arm losses across 20 cancer types, using [~]7,500 tumors from The Cancer Genome Atlas. By analyzing focal deletions and point mutations that co-occur with, or are mutually exclusive with, chromosome-arm losses, we pinpoint 311 candidate drivers associated with 160 cancer type-specific recurrent events. Our approach identifies known aneuploidy drivers such as TP53 and PTEN, while revealing multiple novel candidates, including established tumor suppressor genes not previously linked to aneuploidy. Furthermore, we leverage gene expression changes associated with these chromosome-arm losses to propose pathway-level alterations that may drive cancer progression. Integrating these findings highlights key candidate drivers underlying the observed gene expression alterations, thereby reinforcing their biological relevance. This work provides the first comprehensive catalogue of candidate driver genes for recurrently lost chromosome-arms in human cancer.

cancer biology↗