Biology subjects

Fashemi, B. E.

Publications and source records attributed to Fashemi, B. E..

4 recordsLinked to original sources

bioRxiv2026

Single-cell transcriptomics of heterogeneous patient-derived organoids reveals novel therapeutic targets in high-grade serous ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is characterized by widespread peritoneal dissemination and poor long-term survival, largely driven by metastatic relapse following initial response to chemotherapy. Defining the molecular programs that enable tumor progression from the primary ovarian site to metastatic niches remains a key challenge. Here, we leverage patient-derived organoids (PDOs) coupled with single-cell RNA sequencing (scRNA-seq) to interrogate tumor evolution and identify regulators of metastatic competence in HGSOC. We profiled PDOs and matched formalin-fixed paraffin-embedded (FFPE) tumor samples from ovarian and omental disease sites across seven patients. Single-cell transcriptomic analysis revealed conserved and patient-specific cellular states and enabled reconstruction of inferred trajectories of tumor progression. Comparative trajectory analysis identified gene expression programs associated with metastatic transition from ovarian to omental tumors. Among these, the heparan sulfate proteoglycan AGRIN emerged as a consistently upregulated gene along the metastatic axis. Cell-cell communication analyses suggested that AGRIN-mediated signaling involves both epithelial tumor cells and stromal components, implicating the extracellular matrix in shaping metastatic behavior through mechanotransduction and integrin-associated pathways. Functional validation using genetic depletion of AGRIN in ovarian cancer cell lines demonstrated reduced migratory and invasive capacity, supporting a causal role for AGRIN in promoting metastatic phenotypes. Together, these findings identify AGRIN as a regulator of metastatic competence in HGSOC and highlight extracellular matrix-associated signaling as a key driver of disease progression. More broadly, this study demonstrates that PDO-based single-cell transcriptomic approaches can uncover actionable regulators of metastasis and provide a scalable framework for therapeutic target discovery across cancer types. SignificancePatient-derived organoids analyzed by single-cell transcriptomics reveal dynamic tumor evolution and uncover AGRIN as a regulator of metastatic competence in HGSOC, demonstrating the utility of living tumor models for therapeutic target discovery.

cancer biology↗

bioRxiv2025

Targeting RAD52 overcomes PARP inhibitor resistance in preclinical Brca2-deficient ovarian cancer model

AbstractBRCA-mutated ovarian cancer commonly develops resistance to poly (ADP-ribose) polymerase (PARP) inhibitors. Here, we investigated the DNA repair protein RAD52 as a potential target to overcome resistance. In analysis of The Cancer Genome Atlas datasets and immunohistochemistry of tissue microarrays, elevated RAD52 expression correlated with poor overall survival in patients with high-grade serous ovarian cancers. We tested two PARP inhibitor-resistant Brca2-deficient mouse ovarian cancer models, ID8-OR and HGS2-OR. HGS2- OR cells had higher RAD52 expression than parental lines. Rad52 knockout or knockdown restored PARP inhibitor sensitivity in both models. In syngeneic mice, ID8-OR cells in which Rad52 was knocked out yielded lower tumor burden and longer overall survival than control cells. Rad52 depletion impaired single-strand annealing and homologous recombination and led to accumulation of DNA double-strand breaks after PARP inhibitor treatment. RNA sequencing demonstrated that PARP inhibitor treatment induced Polq expression in Brca2- and Rad52-deficient cells, suggesting a switch to microhomology-mediated end joining. Finally, the RAD52 inhibitor D-I03 synergized with a PARP inhibitor to reduce cell viability and tumor burden and prolong survival. Collectively, our findings establish RAD52 as a promising therapeutic target to overcome PARP inhibitor resistance in BRCA2-mutated ovarian cancer and offer mechanistic insights to inform future clinical strategies.

cancer biology↗

bioRxiv2024

A new role for IFRD1 in regulation of ER stress in bladder epithelial homeostasis

A healthy bladder requires the homeostatic maintenance of and rapid regeneration of urothelium upon stress/injury/infection. Several factors have been identified to play important roles in urothelial development, injury and disease response, however, little is known about urothelial regulation at homeostasis. Here, we identify a new role for IFRD1, a stress-induced gene that has recently been demonstrated to play a critical role in adult tissue proliferation and regeneration, in maintenance of urothelial function/ homeostasis in a mouse model. We show that the mouse bladder expresses IFRD1 at homeostasis and its loss alters the global transcriptome of the bladder with significant accumulation of cellular organelles including multivesicular bodies with undigested cargo, lysosomes and mitochondria. We demonstrate that IFRD1 interacts with several mRNA-translation-regulating factors in human urothelial cells and that the urothelium of Ifrd1-/- mice reveal decreased global translation and enhanced endoplasmic reticulum (ER) stress response. Ifrd1-/- bladders have activation of the unfolded protein response (UPR) pathway, specifically the PERK arm, with a concomitant increase in oxidative stress and spontaneous exfoliation of urothelial cells. Further, we show that such increase in cell shedding is associated with a compensatory proliferation of the basal cells but impaired regeneration of superficial cells. Finally, we show that upon loss of IFRD1, mice display aberrant voiding behavior. Thus, we propose that IFRD1 is at the center of many crucial cellular pathways that work together to maintain urothelial homeostasis, highlighting its importance as a target for diagnosis and/or therapy in bladder conditions.

cell biology↗

bioRxiv2022

D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combatting stress, and decreased regenerative capacity. Multiple diseases including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying how aging affects the urinary tract mucosa and the reason why aging correlates with disease are poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with decreased acid phosphatase activity and shows overall decreased autophagic flux. Aged bladders exhibit basally high accumulation of reactive oxygen species (ROS) and dampened redox response. Furthermore, the aged urothelium exhibits a canonical senescence-associated secretory phenotype (SASP) at baseline with continuous NLRP3-inflammasome- and Gasdermin D (GSDMD)-dependent pyroptotic cell death. Accordingly, we find that aged mice chronically exfoliate epithelial cells. When infected with uropathogenic E. coli, infected aged mice harbor more bacterial reservoirs post-infection and are prone to spontaneous recurrent UTI. Finally, treatment of aged mice with D-Mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses SASP, and limits pyroptotic epithelial shedding. Thus, normal aging dramatically affects bladder physiology with aging alone increasing baseline cellular stress and susceptibility to infection. Additionally, our results suggest that mannose supplementation could serve as a senotherapeutic to limit age-associated urothelial dysfunction.

cell biology↗