Biology subjects

Bahrami, N.

Publications and source records attributed to Bahrami, N..

3 recordsLinked to original sources

bioRxiv2025

CLONAL SELECTION SUPPORTED BY SINGLE CELL DNA SEQUENCING REVEALS HORMONAL ADAPTATION AND RESISTANCE IN LOCALLY ADVANCED BREAST CANCER DURING NEOADJUVANT AROMATASE INHIBITION

BackgroundThe aromatase inhibitors (AI) letrozole and exemestane, are often used in sequence in targeting ER+ breast cancers. However resistance to AI poses a major barrier to sustained clinical benefit, while the biological mechanisms underlying the phenomenon remain largely unknown. In this study, we build on our clinical NeoLetExe trial, with the aim to investigate the molecular basis of resistance to AI, by analysing subclonal evolutionary dynamics during sequential treatment. MethodsWe use whole-exome sequencing (WES) data from 11 ER+ breast cancer patients and 3 timepoints of the Neoletexe trial to reconstruct cancer cell fraction-based subclonal composition. Single-cell DNA sequencing from matched tumour samples is used for validating identified clones and variants. Subclonal variants were annotated to genes by integrating evidence from public data and ExpectoSc. Pathway enrichment analysis using Human Base was conducted. ResultsHigher cancer cell fraction clone trajectories were significantly associated with reduced treatment response (p = 0.023). Clones reconstructed by WES were validated at 81% using single-cell DNA sequencing. Clones resistant to both letrozole and exemestane demonstrated PIK3CA/AKT/mTOR signaling activation, KRAS pathway dysregulation, hedgehog signaling, and androgen receptor pathways, alongside extensive immune activation and metabolic reprogramming. Drug-specific resistance patterns showed exemestane-resistant clones enriched for epigenetic control and miRNA-mediated silencing, while letrozole-resistant clones displayed metabolic dysregulation but notably lacked immune pathway activation. In contrast, treatment-sensitive clones maintained coordinated cell cycle control, preserved DNA damage responses, and retained immune signaling capacity. Analysis of FDA-approved breast cancer targets identified actionable alterations in PIK3CA (4 patients) and AKT1 (1 patient) that persisted through AI treatment, with RNA expression analysis revealing 48 additional therapeutic targets spanning PI3K/AKT/mTOR, CDK4/6, DNA repair (BRCA1/2, ATM), and immune checkpoint pathways. ConclusionWES-based cancer cell fraction analysis successfully captured subclonal evolutionary trajectories during AI treatment, revealing drug-specific mechanisms and identifying key molecular players in endocrine therapy resistance. This work establishes a framework for precision oncology approaches by providing actionable therapeutic targets and advancing our understanding of resistance mechanisms to improve clinical outcomes in sequential AI therapy.

cancer biology↗

bioRxiv2019

Development of vascular myogenic responses in zebrafish

The vascular system is placed under enormous stress at the onset of cardiac contractility and blood flow. Nascent blood vessel tubes initially consist of a thin endothelial wall and rapidly acquire support from mural cells (pericytes and vascular smooth muscle cells; vSMCs). Following their association with vessels, mural cells acquire vasoactive ability (contraction and relaxation). However, we have little information as to when this vasoactivity first develops, and the extent to which each mural cell type contributes to vascular tone regulation during development. For the first time in an in vivo system, we highlight the dynamic changes in mural cell vasoactivity during development. We assess mural cell vasoactivity in the early zebrafish cerebral vasculature in response to pharmacological agents. We determine that pericyte-covered vessels constrict and dilate at 4 days post fertilization (dpf) but not at 6 dpf. The prostaglandin EP4 receptor contributes to pericyte-covered vessel dilation at 4 dpf. In contrast, vSMC-covered vessels constrict but do not dilate at 4 dpf. At 6 dpf, vSMC-covered vessels continue to constrict but only dilate from a pre-constricted state. Using genetic ablation, we demonstrate that mural cell contraction and relaxation is an active response by pericytes and vSMCs. Thus, we show that both pericytes and vSMCs have the ability to regulate cerebral vascular tone but at different stages of development. Pericytes are involved in regulating vessel diameters prior to the maturation of the vSMCs. Once vSMCs mature, pericytes are no longer active, and only vSMCs regulate vascular tone in the developing embryonic brain of zebrafish. The onset of vasoactivity of vSMCs corresponds to the development of increased neuronal activity and neurovascular coupling.

developmental biology↗

bioRxiv2018

Scarless repair of acute and chronic kidney injury in African Spiny mice (Acomys cahirinus)

Solid organ fibrosis is a major burden on global health and medical care costs. Muroid rodents of the genus Acomys (African Spiny mice) are terrestrial mammals that evolved remarkable abilities to regenerate severe skin wounds without scar formation. However, whether scar-free wound repair in Acomys extends beyond skin to vital internal organs is not known. Here, we used two aggressive kidney injury models known to produce severe renal fibrosis and show that despite equivalent acute kidney injury, there was rapid restoration of nephron structure and function without fibrosis in Acomys compared to extensive fibrosis leading to renal failure in Mus musculus. These results suggest Acomys species have evolved genomic adaptations for wound healing that activate regenerative repair pathways not only in skin, but also in vital internal organs. Our findings have important implications for discovering a long-sought evolutionary solution to internal organ injury and regeneration.

pathology↗