Biology subjects

Moquin-Beaudry, G.

Publications and source records attributed to Moquin-Beaudry, G..

9 recordsLinked to original sources

bioRxiv2026

A human lung organoid co-culture model of early bone sarcoma metastasis reveals contact-dependent epithelial remodeling at the metastatic interface

Lung metastasis drives mortality across cancer types, yet how infiltrating tumor cells remodel the lung epithelium to establish metastatic niches remains poorly understood. Here we establish MESCUL (MEtastatic Sarcoma Co-CULture), a co-culture platform combining human lung organoids with patient-derived bone sarcoma cells to model early tumor-lung epithelial interactions in a physiologically relevant 3D system. MESCUL reveals that direct tumor-epithelial contact induces rapid, reproducible lung epithelial remodeling across Ewing sarcoma (ES) and osteosarcoma (OS) models and multiple organoid donor backgrounds, which is contact-dependent and not recapitulated by paracrine signaling. Single-cell RNA sequencing identifies LIMES (Lung Interface Metastasis Signature), a shared transcriptional program encompassing focal adhesion assembly, matrix metalloprotease (MMP) upregulation, and emergence of a damage-associated transitional cell state, in both ES and OS. Mechanistically, tumor-derived fibronectin (FN1) engages epithelial integrin receptors to activate focal adhesion kinase (FAK), driving amphiregulin (AREG) induction and MMP-mediated remodeling; FN1 alone phenocopies this response, and FAK inhibition attenuates it, nominating the FN1-integrin-FAK-AREG axis as a candidate therapeutic vulnerability. The LIMES program, identified through the MESCUL co-culture model, is spatially confined to the tumor-lung interface in patient metastases of both ES and OS, as demonstrated by spatial transcriptomics across nine patients. Massons trichrome staining of matched patient sections reveals pronounced collagen deposition in the peri-tumoral lung parenchyma, consistent with LIMES acting upstream of a wound-healing cascade that proceeds to structural fibrotic remodeling in patient tissue. Together, these findings establish the lung epithelium as an active participant in metastatic colonization, characterize a pharmacologically targetable, spatially restricted epithelial remodeling response at the bone sarcoma-lung interface across OS and ES, and introduce MESCUL as a tractable 3D platform for investigating lung metastasis, with possible implications for tumor types beyond bone sarcomas.

cancer biology↗

bioRxiv2025

Off-the-Shelf Engineered Liver Tissue Reverses Acute Liver Failure Without Immunosuppression

There is an urgent need for effective solutions to replace liver functions in patients with acute liver failure (ALF). We describe here a human engineered liver tissue composed of induced pluripotent stem cell (iPSC)-derived liver organoids encapsulated within a non-degradable biomaterial. Unlike most stem cell-derived products, this encapsulated liver tissue (ELT) achieves functional maturation during manufacturing. When transiently implanted into the peritoneal cavity of immunocompetent mice with ALF, the human ELT improves survival, treats hepatic encephalopathy and promotes liver regeneration, without requiring immunosuppression. Based on robust processes and designed to overcome challenges such as foreign body reaction, loss of function and cryopreservation, the ELT does not require vascularization and provides immediate and long-lasting functional replacement. Once the liver regenerated, the ELT is explanted, leaving the subjects cured. Macroencapsulation prevents rejection by shielding the organoids from the host immune system, and minimizes the risk of tumorigenicity. The data shown demonstrate the ELTs potential to be developed into a safe and effective off-the-shelf treatment that, if validated in upcoming clinical trials, could replace liver transplantation for many patients with ALF.

bioengineering↗

bioRxiv2024

Ketogenic interventions restore cognition and modulate peripheral metabolic dysfunctions in Alzheimer's disease mouse models

Lifestyle factors modulate dementia risk. We investigated mechanisms of dementia risk reduction by emerging dietary ketogenic interventions. We show that distinct interventions, a medium-chain triglycerides (MCT)-enriched diet and a carbohydrate-free, high-fat diet (CFHF), improve cognition and dendritic spine density of memory-associated hippocampal neurons in two mouse models of Alzheimers disease (AD). Only the CFHF diet drove increased circulating ketones, suggesting distinct underlying mechanisms. AD mice exhibited baseline and diet-induced susceptibility to peripheral metabolic disturbances that were improved by MCT and exacerbated by CFHF diets. Prominent AD-associated dysregulation of the liver transcriptome was largely restored by both interventions, but MCT also downregulated lipogenic enzymes and did not trigger a CFHF-like inflammatory signature. Novel AD- and diet-induced plasmatic changes in hormones and lipid species were identified. Thus, different ketogenic interventions yield cognitive benefits in AD models while showing intervention-specific modulation of peripheral metabolic defects, with implications for design of therapeutic ketogenic strategies.

neuroscience↗

bioRxiv2024

Mapping the peripheral immune landscape of Parkinson's disease patients with single-cell sequencing

Parkinsons Disease (PD) is most recognized for its impact on the central nervous system. However, recent breakthroughs underscore the crucial role of interactions between central and peripheral systems in PDs pathogenesis. The spotlight is now shifting as we explore beyond the central nervous system, discovering that peripheral changes such as inflammatory dysfunctions may predict the rate of disease progression and severity. Despite more than 200 years of research on PD, reliable diagnostic or progression biomarkers and effective disease-modifying treatments are still lacking. Additionally, the cellular mechanisms that drive changes in immunity are largely unknown. Thus, understanding peripheral immune signatures could lead to earlier diagnosis and more effective treatments for PD. Here, we sought to define the transcriptomic alterations of the complete peripheral immune cell compartment by single-cell RNA- and T-cell receptor-sequencing with hopes of uncovering PD signatures and potential peripheral blood biomarkers. Following transcriptional profiling of 78 876 cells from 10 healthy controls and 14 PD donors, we observed five major classes of immune cell types; myeloid (monocytes, dendritic cells) and lymphoid (T, B, natural killer) cells from which we identified 38 cellular subtypes following bioinformatic re-clustering. Comparing immune cell subtypes and phenotypes between PD patients and healthy controls revealed notable features of PD: 1) a significant shift of classical CD14+ monocytes towards an activated CD14+/CD83+ state, 2) changes in lymphocyte subtype abundance, including a significant decrease in CD4+ naive and mucosal-associated invariant T-cells subtypes, along with an increase in CD56+ natural killer cells, 3) the identification by T-cell receptor sequencing of several PD specific T-cell clones shared between multiple patients, suggesting the implication of common epitopes in PD pathogenesis, 4) a notable increase in the expression of activation signature genes, including the AP-1 stress-response transcription factor complex, across all PD cell types. This signal was not present in atypical parkinsonism patients with multiple systems atrophy or progressive supranuclear palsy. Overall, we present a comprehensive atlas of peripheral blood mononuclear cells from control and PD patients which should serve as a tool to improve our understanding of the role the immune cell landscape plays in PD pathogenesis.

genetics↗

bioRxiv2024

Senescent fibroblasts support tumor growth by inducing immune cell death in humanized models

Syngeneic mouse tumor models have shown that senescence influences the tumor immune response in multiple ways, including the induction of an immunosuppressive microenvironment or the promotion of immune cell recruitment. Yet, the impact of senescence on the tumor immune response in a humanized setting remains largely unexplored. To address this, we employed tumor spheroids and mice bearing tumors immunogenic to human immune cells derived from the same donor. We found that senescent fibroblasts exert a dual effect by enhancing the recruitment of immune cells into the tumor microenvironment while simultaneously promoting the apoptosis of T and NK cells. Mechanistically, we demonstrate that this apoptosis is primarily due to increased Fas ligand (FasL) expression on the surface of senescent fibroblasts. Deletion of FasL on fibroblasts was sufficient to prevent immune cell death and increase tumor cell killing. Our results highlight the importance of evaluating the impact of therapy-induced senescence in humanized models to understand and predict the outcome of cancer treatments.

cancer biology↗

bioRxiv2023

CellsFromSpace: A versatile tool for spatial transcriptomic data analysis with reference-free deconvolution and guided cell type/activity annotation

Spatial transcriptomics involves capturing the transcriptomic profiles of millions of cells within their spatial contexts, enabling the analysis of cell crosstalk in healthy and diseased organs. However, spatial transcriptomics also raises new computational challenges for analyzing multidimensional data associated with spatial coordinates. In this context, we introduce a novel framework called CellsFromSpace. This framework allows users to analyze various commercially available technologies without relying on a single-cell reference dataset. Based on the independent component analysis, CellsFromSpace decomposes spatial transcriptomic data into components that represent distinct cell types or activities. Here, we demonstrate that CellsFromSpace outperforms previous reference-free deconvolution tool in term of accuracy and speed, and successfully identify spatially distributed cells as well as rare diffuse cells on datasets from the Visium, Slide-seq, MERSCOPE, and COSMX technologies. The framework provides a user-friendly graphical interface that enables non-bioinformaticians to perform a full analysis and to annotate the components based on marker genes and spatial distributions. Additionally, CellsFromSpace offers the capability to reduce noise or artifacts by component selection and supports analyses on multiple datasets simultaneously. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/555558v2_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@67f64eorg.highwire.dtl.DTLVardef@15ba940org.highwire.dtl.DTLVardef@c4d9a8org.highwire.dtl.DTLVardef@1ade390_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2021

Autologous humanized mouse models of iPSC-derived tumors allow for the evaluation and modulation of cancer-immune cell interactions

Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or iPSC-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that either fibroblastic, hepatic or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cell suggesting rapid establishment of an immunosuppressive microenvironment. Inhibition of PD-1 by Nivolumab in humanized mice resulted in an increased immune cell infiltration and a slight decrease in tumor growth. We expect these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types. SIGNIFICANCE STATEMENTPreclinical models capable of providing an environment where human tumors are confronted with autologous immune cells are not easily accessible and limit drug development. As an alternative we generated genetically-defined tumor cell lines from primary and iPSC-derived cells for the evaluation of cancer-immune cell interactions in autologous humanized mice.

cancer biology↗

bioRxiv2019

The tumor immune response is not compromised by mesenchymal stromal cells in humanized mice

Therapeutic uses of mesenchymal stromal cells (MSCs) have emerged over the past decade. Yet, their effect on tumor growth remains highly debated, particularly in an immune competent environment. Here, we wanted to investigate the impact of human umbilical cord MSCs (hUC-MSCs) on tumor growth in humanized mice generated by the adoptive transfer of peripheral blood mononuclear cells (Hu-AT) or the co-transplantation of hematopoietic stem cells and human thymic tissue (Hu-BLT). Our results showed that the growth and immune rejection of engineered human tumors was not altered by the injection of hUC-MSCs in immune-deficient or humanized mice respectively. This was observed whether tumor cells were injected subcutaneously or intravenously and independently of the injection route of the hUC-MSCs. Moreover, only in Hu-BLT mice did hUC-MSCs have some effects on the tumor immune infiltrate, yet without altering tumor growth. These results demonstrate that hUC-MSCs do not promote tumor growth and neither do they prevent tumor infiltration and rejection by immune cells in humanized mice.

cell biology↗

bioRxiv2018

Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases

Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.

pharmacology and toxicology↗