Biology subjects

Ors, A.

Publications and source records attributed to Ors, A..

3 recordsLinked to original sources

bioRxiv2025

Claustrum volume in human lifespan trajectory and effect of age, hemisphere, and sex

The human claustrum is a bilateral, thin, irregularly shaped gray matter structure located between the striatum and insula. While previous research demonstrated the effect of distinct medical conditions, such as prematurity, schizophrenia, and Alzheimers disease, on claustrum function and structure, it is poorly understood how non-pathologic biological conditions effect the claustrum. This study aimed to investigate the effect of age, hemisphere, and sex on claustrum volume. We used T1-weighted 3 Tesla MRI scans of 3,474 healthy participants ranging from 1 to 80 years of age, deep learning-based automated claustrum segmentation, and a normative modeling approach to delineate lifespan trajectories of claustrum volumes for both hemispheres and sexes. Additionally, ordinary least squares regression analyses were applied to further characterize age, hemisphere, and sex effect. Lifespan analysis revealed a trajectory of rapid claustrum volume increase from infancy to adolescence ([~] 1-15 years, annual growth 39.300 mm3/year), a plateau phase from early to middle adulthood ([~] 15-40 years, annual change 0.153 mm3/year), and a subsequent decline from middle adulthood to old age ([~] 40-80 years, annual decrease 10.325 mm3/year). The right claustrum was on average larger than the left one across all ages. Finally, overall, females had larger total intracranial volume-adjusted claustrum volumes than males across the lifespan. Results demonstrate a distinct effect of age, hemisphere, and sex on claustrum volume. Data provide a comprehensive framework for sex- and hemisphere-sensitive claustrum structure lifespan trajectories relevant for studying neurodevelopmental and neurodegenerative effects on the claustrum.

neuroscience↗

bioRxiv2022

Low HER2 enables dedifferentiation and transformation of normal breast epithelial cells via chromatin opening

Overexpression of the human epidermal growth factor 2 (HER2) protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. Despite significant advances in the development of targeted therapies and improvements in the 5-year survival rate of metastatic HER2-positive breast cancer patients, a better understanding of the disease at an early stage is needed to prevent its progression. Here, we used an inducible breast cancer transformation system that allows investigation of early molecular changes at high temporal resolution. HER2 overexpression to similar levels as those observed in a subtype of HER2 positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during the first few hours of HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with a wave of chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. We observed that HER2 overexpression leads to reprogramming of many distal regulatory regions and promotes reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype. Our data provide a discovery platform for signalling to chromatin pathways in HER2-driven cancers, offering an opportunity for biomarker discovery and identification of novel drug targets.

cancer biology↗

bioRxiv2022

A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and strongly hormone receptor positive. Yet, they are relatively resistant to tamoxifen and are associated with inferior long-term outcomes compared to invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. Through a comprehensive analysis of the epigenome of ILC in pre-clinical models and clinical samples we found that compared to IDC, ILC has a distinct chromatin state that is linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This results in an ILC-unique FOXA1-estrogen receptor (ER) axis that promotes the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis leads to retained ER chromatin binding after tamoxifen treatment thereby facilitating tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the auto-induction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, we show that ILC is characterized by a unique cell state and FOXA1-ER axis that dictate tumor progression and offer a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC to optimize endocrine treatments in this breast cancer subtype.

cancer biology↗