Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer

Galhenage, Pamoda; Zhou, Yunlan; Perry, Erica; Loc, Brenda; Fietz, Kelly; Iyer, Sonia; Reinhardt, Ferenc; Da Silva, Tiego; Botchkarev, Vladimir; Chen, Jie; Crum, Christopher P.; Weinberg, Robert A.; Pathania, Shailja

doi:10.1016/j.celrep.2023.113144

Cited by 2 publications

(1 citation statement)

References 75 publications

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“…TP53 is known to regulate G1 phases, limiting cell division and proliferation when DNA damage occurs, whereas TP53 mutations diminish G0/G1 phase arrest and apoptosis, causing replication fork damage, genomic instability, and DSB accumulation [53,57,58]. This is particularly important for the FTE, as previous research has suggested that the FTE has a weaker response and repair capacity to replication stress than the OSE [59]. In addition, the FTE is more susceptible to irritants such as follicular fluid [60].…”

Section: Discussionmentioning

confidence: 99%

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Dai,

Xu,

Gong

et al. 2024

IJMS

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RAD51D mutations have been implicated in the transformation of normal fallopian tube epithelial (FTE) cells into high-grade serous ovarian cancer (HGSOC), one of the most prevalent and aggressive gynecologic malignancies. Currently, no suitable model exists to elucidate the role of RAD51D in disease initiation and progression. Here, we established organoids from primary human FTE and introduced TP53 as well as RAD51D knockdown to enable the exploration of their mutational impact on FTE lesion generation. We observed that TP53 deletion rescued the adverse effects of RAD51D deletion on the proliferation, stemness, senescence, and apoptosis of FTE organoids. RAD51D deletion impaired the homologous recombination (HR) function and induced G2/M phase arrest, whereas concurrent TP53 deletion mitigated G0/G1 phase arrest and boosted DNA replication when combined with RAD51D mutation. The co-deletion of TP53 and RAD51D downregulated cilia assembly, development, and motility, but upregulated multiple HGSOC-associated pathways, including the IL-17 signaling pathway. IL-17A treatment significantly improved cell viability. TP53 and RAD51D co-deleted organoids exhibited heightened sensitivity to platinum, poly-ADP ribose polymerase inhibitors (PARPi), and cell cycle-related medication. In summary, our research highlighted the use of FTE organoids with RAD51D mutations as an invaluable in vitro platform for the early detection of carcinogenesis, mechanistic exploration, and drug screening.

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Section: Discussionmentioning

confidence: 99%

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Dai,

Xu,

Gong

et al. 2024

IJMS

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Integrated analysis of spatial transcriptomics and CT phenotypes for unveiling the novel molecular characteristics of recurrent and non-recurrent high-grade serous ovarian cancer

Ju,

Youn,

Kang

et al. 2024

Biomark Res

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Background High-grade serous ovarian cancer (HGSOC), which is known for its heterogeneity, high recurrence rate, and metastasis, is often diagnosed after being dispersed in several sites, with about 80% of patients experiencing recurrence. Despite a better understanding of its metastatic nature, the survival rates of patients with HGSOC remain poor. Methods Our study utilized spatial transcriptomics (ST) to interpret the tumor microenvironment and computed tomography (CT) to examine spatial characteristics in eight patients with HGSOC divided into recurrent (R) and challenging-to-collect non-recurrent (NR) groups. Results By integrating ST data with public single-cell RNA sequencing data, bulk RNA sequencing data, and CT data, we identified specific cell population enrichments and differentially expressed genes that correlate with CT phenotypes. Importantly, we elucidated that tumor necrosis factor-α signaling via NF-κB, oxidative phosphorylation, G2/M checkpoint, E2F targets, and MYC targets served as an indicator of recurrence (poor prognostic markers), and these pathways were significantly enriched in both the R group and certain CT phenotypes. In addition, we identified numerous prognostic markers indicative of nonrecurrence (good prognostic markers). Downregulated expression of PTGDS was linked to a higher number of seeding sites (≥ 3) in both internal HGSOC samples and public HGSOC TCIA and TCGA samples. Additionally, lower PTGDS expression in the tumor and stromal regions was observed in the R group than in the NR group based on our ST data. Chemotaxis-related markers (CXCL14 and NTN4) and markers associated with immune modulation (DAPL1 and RNASE1) were also found to be good prognostic markers in our ST and radiogenomics analyses. Conclusions This study demonstrates the potential of radiogenomics, combining CT and ST, for identifying diagnostic and therapeutic targets for HGSOC, marking a step towards personalized medicine.

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Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer

Cited by 2 publications

References 75 publications

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Human Fallopian Tube-Derived Organoids with TP53 and RAD51D Mutations Recapitulate an Early Stage High-Grade Serous Ovarian Cancer Phenotype In Vitro

Integrated analysis of spatial transcriptomics and CT phenotypes for unveiling the novel molecular characteristics of recurrent and non-recurrent high-grade serous ovarian cancer

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