Publications by authors named "Moloud Ahmadi"

8 Publications

  • Page 1 of 1

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Cell 2020 06 22;181(6):1329-1345.e24. Epub 2020 May 22.

The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
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http://dx.doi.org/10.1016/j.cell.2020.04.047DOI Listing
June 2020

Nanostructured Architectures Promote the Mesenchymal-Epithelial Transition for Invasive Cells.

ACS Nano 2020 05 11;14(5):5324-5336. Epub 2020 May 11.

Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, M5S 3G9, Canada.

Dynamic modulation of cellular phenotypes between the epithelial and mesenchymal states-the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET)-plays an important role in cancer progression. Nanoscale topography of culture substrates is known to affect the migration and EMT of cancer cells. However, existing platforms heavily rely on simple geometries such as grooved lines or cylindrical post arrays, which may oversimplify the complex interaction between cells and nanotopography . Here, we use electrodeposition to construct finely controlled surfaces with biomimetic fractal nanostructures as a means of examining the roles of nanotopography during the EMT/MET process. We found that nanostructures in the size range of 100 to 500 nm significantly promote MET for invasive breast and prostate cancer cells. The "METed" cells acquired distinct expression of epithelial and mesenchymal markers, displayed perturbed morphologies, and exhibited diminished migration and invasion, even after the removal of a nanotopographical stimulus. The phosphorylation of GSK-3 was decreased, which further tuned the expression of Snail and modulated the EMT/MET process. Our findings suggest that invasive cancer cells respond to the geometries and dimensions of complex nanostructured architectures.
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http://dx.doi.org/10.1021/acsnano.9b07350DOI Listing
May 2020

Detection of pathogenic bacteria via nanomaterials-modified aptasensors.

Biosens Bioelectron 2020 Feb 28;150:111933. Epub 2019 Nov 28.

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada. Electronic address:

Detection and identification of special cells via aptamer-based nano-conjugates sensors have been revolutionized over the past few years. These sensing platforms rely on selecting aptamers using systematic evolution of ligands by exponential enrichment (SELEX) in vitro, which allows for sensitive detection of cells. Integration of the aptamer-based sensors (aptasensors) with nanomaterials offers enhanced specificity and sensitivity, which in turn, offers great promise for numerous applications, spanning from bioanalysis to biomedical applications. Accordingly, the demand for using aptamer-conjugated nanomaterials for various applications has progressively increased over the past years. In light of this, this Review seeks to highlight the recent advances in the development of aptamer-conjugated nanomaterials and their utilization for the detection of various pathogens involved in infectious diseases and food contamination.
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http://dx.doi.org/10.1016/j.bios.2019.111933DOI Listing
February 2020

Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.

Cell Rep 2019 04;27(3):971-986.e9

Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Glioblastoma therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells (GSCs) to interrogate function of the coding genome, we identify actionable pathways responsible for growth, which reveal the gene-essential circuitry of GBM stemness and proliferation. In particular, we characterize members of the SOX transcription factor family, SOCS3, USP8, and DOT1L, and protein ufmylation as important for GSC growth. Additionally, we reveal mechanisms of temozolomide resistance that could lead to combination strategies. By reaching beyond static genome analysis of bulk tumors, with a genome-wide functional approach, we reveal genetic dependencies within a broad range of biological processes to provide increased understanding of GBM growth and treatment resistance.
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http://dx.doi.org/10.1016/j.celrep.2019.03.047DOI Listing
April 2019

Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells.

Genes Dev 2019 05 6;33(9-10):498-510. Epub 2019 Mar 6.

Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnt GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wnt cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.
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http://dx.doi.org/10.1101/gad.321968.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499328PMC
May 2019

Three-Dimensional Nanostructured Architectures Enable Efficient Neural Differentiation of Mesenchymal Stem Cells via Mechanotransduction.

Nano Lett 2018 11 18;18(11):7188-7193. Epub 2018 Oct 18.

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada.

Cell morphology and geometry affect cellular processes such as stem cell differentiation, suggesting that these parameters serve as fundamental regulators of biological processes within the cell. Hierarchical architectures featuring micro- and nanotopographical features therefore offer programmable systems for stem cell differentiation. However, a limited number of studies have explored the effects of hierarchical architectures due to the complexity of fabricating systems with rationally tunable micro- and nanostructuring. Here, we report three-dimensional (3D) nanostructured microarchitectures that efficiently regulate the fate of human mesenchymal stem cells (hMSCs). These nanostructured architectures strongly promote cell alignment and efficient neurogenic differentiation where over 85% of hMSCs express microtubule-associated protein 2 (MAP2), a mature neural marker, after 7 days of culture on the nanostructured surface. Remarkably, we found that the surface morphology of nanostructured surface is a key factor that promotes neurogenesis and that highly spiky structures promote more efficient neuronal differentiation. Immunostaining and gene expression profiling revealed significant upregulation of neuronal markers compared to unpatterned surfaces. These findings suggest that the 3D nanostructured microarchitectures can play a critical role in defining stem cell behavior.
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http://dx.doi.org/10.1021/acs.nanolett.8b03313DOI Listing
November 2018

5'-AMP-Activated Protein Kinase Signaling in Caenorhabditis elegans.

Exp Suppl 2016;107:375-388

Department of Biology, McGill University, 1205 Avenue Docteur Penfield, Montreal, QC, Canada, H3A 1B1.

AMP-activated protein kinase (AMPK) is one of the central regulators of cellular and organismal metabolism in eukaryotes. Once activated by decreased energy levels, it induces ATP production by promoting catabolic pathways while conserving ATP by inhibiting anabolic pathways. AMPK plays a crucial role in various aspects of cellular function such as regulating growth, reprogramming metabolism, autophagy, and cell polarity. In this chapter, we focus on how recent breakthroughs made using the model organism Caenorhabditis elegans have contributed to our understanding of AMPK function and how it can be utilized in the future to elucidate hitherto unknown aspects of AMPK signaling.
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http://dx.doi.org/10.1007/978-3-319-43589-3_15DOI Listing
June 2017

AMPK acts as a molecular trigger to coordinate glutamatergic signals and adaptive behaviours during acute starvation.

Elife 2016 09 19;5. Epub 2016 Sep 19.

Department of Biology, McGill University, Montreal, Canada.

The stress associated with starvation is accompanied by compensatory behaviours that enhance foraging efficiency and increase the probability of encountering food. However, the molecular details of how hunger triggers changes in the activity of neural circuits to elicit these adaptive behavioural outcomes remains to be resolved. We show here that AMP-activated protein kinase (AMPK) regulates neuronal activity to elicit appropriate behavioural outcomes in response to acute starvation, and this effect is mediated by the coordinated modulation of glutamatergic inputs. AMPK targets both the AMPA-type glutamate receptor GLR-1 and the metabotropic glutamate receptor MGL-1 in one of the primary circuits that governs behavioural response to food availability in C. elegans. Overall, our study suggests that AMPK acts as a molecular trigger in the specific starvation-sensitive neurons to modulate glutamatergic inputs and to elicit adaptive behavioural outputs in response to acute starvation.
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http://dx.doi.org/10.7554/eLife.16349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028190PMC
September 2016
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