Biology subjects

Qadan, M.

Publications and source records attributed to Qadan, M..

4 recordsLinked to original sources

bioRxiv2025

Single-cell transcriptomics reveals the impact of sex and age in the healthy human liver

Background & AimsThe liver is a vital organ composed of parenchymal, nonparenchymal, and immune cell populations. Single-cell sequencing approaches now provide the opportunity to understand how sex and age influence gene expression and cellular function across cell types within the liver. MethodsWe analyzed the cellular composition and interactions for the human liver through single-nucleus RNA sequencing (snRNA-seq), incorporating insights from 37 healthy liver samples. The dataset contains cells from female and male donors spanning more than seven decades of life, and analysis was performed to evaluate the impact of sex and age on differential gene expression, pathway enrichment, and predicted ligand-receptor and protein-protein interactions. ResultsExcluding the X and Y chromosomes, we identified 374 genes uniquely enriched in cells of the female liver and 520 genes enriched in cells of the male liver. Differential expression analysis defined unique circuitries enriched within each cell type between females and males and their impact on cell-cell communication and response to external signals, including enrichment of cholesterol/lipid metabolism, transforming growth factor beta (TGF-beta) signaling, and fibronectin (FN1) production in female cells and bone morphogenic protein (BMP) signaling in male cells. With increased age, we observe a greater diversity in gene expression, including enrichment of genes that regulate neuregulin (NGR) signaling at older ages, while genes regulating insulin growth factor (IGF) signaling are enriched at younger ages. Senescence signatures were also identified for each cell type within the liver. ConclusionsThese results define the activities of healthy cell types within the liver across sex and age and provide a foundation for studies to examine how ancestry, geography, and disease states influence liver function within these contexts. Impact and ImplicationsOur study analyzes 37 human liver samples at the single-cell level to understand how sex and age influence gene expression, cell interactions, and response to signals across liver cell types and sub-types. These findings are of particular significance for researchers who need to understand how sex and age may influence the response of individual cell types to injury or treatment of injury. This dataset will also provide a healthy reference for future studies to understand how ancestry, geography, and disease states shape liver biology across age and sex.

cell biology↗

bioRxiv2024

Molecular Magnetic Resonance Imaging of Dysregulated Zinc Secretion Detects Early Pancreatic Ductal Adenocarcinoma Lesions and Response to KRASG12D Inhibitor Treatment

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, primarily due to late-stage diagnosis and limited treatment options. Zinc homeostasis is markedly dysregulated in PDAC and this dysregulation can be probed by administering a secretagogue to stimulate zinc secretion (SSZS) in the exocrine pancreas and imaging this secretion with a zinc sensitive MRI probe. This study demonstrates the potential of SSZS MRI for early detection, monitoring treatment response, and assessing recurrence after treatment withdrawal in PDAC. Our approach relies on interrogating the pancreas, circumventing the challenge of locating small, elusive tumors. By SSZS MRI, we detected PDAC by observing the unique zinc hypersecretory activity of the pancreas when malignancy is present. We observed dysregulation of zinc transporters in both human and mouse pancreas containing PDAC and confirmed secretagogue-stimulated zinc secretion in vitro and in vivo. We found that combining secretagogues such as secretin and caerulein maximized zinc secretion and as such MRI signal in the pancreas. Notably, SSZS MRI detected treatment responses to KRAS G12D inhibition within 3-5 days and identified cancer recurrence as early as one day post-treatment withdrawal. Additionally, secretagogue stimulation improved treatment responses and delayed recurrence in both treatment models. These findings suggest that SSZS MRI could significantly enhance PDAC diagnosis and management, providing a novel, non-invasive imaging modality to improve patient outcomes. STATEMENT OF SIGNIFICANCEThis study demonstrates the utility of secretagogue-stimulated zinc secretion (SSZS) MRI in detecting pancreatic ductal adenocarcinoma (PDAC) at early stages, monitoring treatment responses, and assessing cancer recurrence, thereby offering a promising non-invasive imaging modality to improve PDAC patient management and outcomes.

cancer biology↗

bioRxiv2023

Precision-Cut Liver Slices as an ex vivo model to evaluate antifibrotic therapies for liver fibrosis and cirrhosis

BackgroundPrecision-Cut Liver Slices (PCLS) are an ex vivo culture model developed to study hepatic drug metabolism. One of the main benefits of this model is that it retains the structure and cellular composition of the native liver. PCLS also represents a potential model system to study liver fibrosis in a setting that more closely approximates in vivo pathology than in vitro methods. The aim of this study was to assess whether responses to antifibrotic interventions can be detected and quantified with PCLS. MethodsPCLS of 250 m thickness were prepared from four different murine fibrotic liver models: choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), thioacetamide (TAA), diethylnitrosamine (DEN), and carbon tetrachloride (CCl4). PCLS were treated with 5 M Erlotinib for 72 hours. Histology and gene expression were then compared with in vivo murine experiments and TGF-{beta}1 activated hepatic stellate cells (HSCs). These types of PCLS characterization were also evaluated in PCLS from human cirrhotic liver. ResultsPCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGFR inhibitor significantly inhibited the expression of profibrogenic genes Il6, Col1a1 and Timp1 in PCLS from CDAHFD-induced cirrhotic mice, and Il6, Col1a1 and Tgfb1 in PCLS from TAA-induced cirrhotic rats. Erlotinib treatment of PCLS from DEN-induced cirrhotic rats inhibited the expression of Col1a1, Timp1, Tgfb1 and Il6, which was consistent with the impact of erlotinib on Col1a1 and Tgfb1 expression in in vivo DEN-induced cirrhosis. Erlotinib treatment of PCLS from CCl4-induced cirrhosis caused reduced expression of Timp1, Col1a1 and Tgfb1, which was consistent with the effect of erlotinib in in vivo CCl4-induced cirrhosis. In addition, in HSCs at PCLS from normal mice, TGF-{beta}1 treatment upregulated Acta2 (SMA), while treatment with erlotinib inhibited the expression of Acta2. Similar expression results were observed in TGF-{beta}1 treated in vitro HSCs. Expression of MMPs and TIMPs, key regulators of fibrosis progression and regression, were also significantly altered under erlotinib treatment in PCLS. Expression changes under erlotinib treatment were also corroborated with PCLS from human cirrhosis samples. ConclusionThe responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observed in vivo and in vitro. Similar effects were also reproduced in PCLS derived from patients with cirrhosis. PCLS is an excellent model to assess antifibrotic therapies that is aligned with the principles of Replacement, Reduction and Refinement (3Rs).

cell biology↗

bioRxiv2023

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

cancer biology↗