Biology subjects

Courtois, E. T.

Publications and source records attributed to Courtois, E. T..

6 recordsLinked to original sources

bioRxiv2025

High-Resolution Spatial Transcriptomics Reveals Fibroblast and Neuroimmune Microenvironments in Endometriosis Lesions

Endometriosis is a chronic, systemic, inflammatory disease characterized by the presence of endometrium-like tissue growing outside of the uterus. One of its main symptoms is chronic pain and inflammation leading to a decreased quality of life. This is a common disease, as at least one in ten female-born individuals have endometriosis. Yet the understanding of the mechanisms that drive pain symptoms and disease progression remain poorly defined. This study establishes the precise spatial transcriptomic cartography of human ovarian and peritoneal lesions, two of the most commonly found lesions. We identified shared spatial features across lesion types, including immune cell infiltration, fibroblast specific compartments surrounding epithelial glands, and distinct distributions of neuronal and macrophage subsets. We precisely defined sensory neuronal subtypes, and mapped their spatial location relative to immune cells. We further validate the epithelial-neuronal interactome, using an in vitro 3D model of peripheral sensory brain organoids co-cultured with human endometriosis epithelial and fibroblast cells. By mapping spatial cellular interactions and identifying conserved features across lesion types linked to pain, our study provides emerging insights into endometriosis pathophysiology, paving the way for the development of novel targeted therapeutic strategies.

cell biology↗

bioRxiv2024

Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.

cancer biology↗

bioRxiv2024

Single-cell analysis identifies distinct macrophage phenotypes associated with pro-disease and pro-resolving functions in the endometriotic niche

Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in non-hormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumour-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6 and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodelling. We also described a population of pro-resolving large peritoneal macrophages (LpM) that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open new avenues for the treatment of endometriosis.

immunology↗

bioRxiv2023

Immunosuppressive tumor microenvironment of osteosarcoma

Osteosarcoma is the most common malignant bone tumor in children, characterized by a high degree of genomic instability, resulting in copy-number alterations and genomic rearrangements without disease-defining recurrent mutations. Clinical trials based on molecular characterization have failed to find new effective therapies or improve outcomes over the last 40 years. To better understand the immune microenvironment of osteosarcoma, we performed single-cell RNA sequencing on six tumor biopsy samples, combined with a previously-published cohort of six samples. Additional osteosarcoma samples were profiled using spatial transcriptomics for validation of discovered subtypes and to add spatial context. Analysis revealed immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory and exhausted T-cells, and LAMP3+ dendritic cells. Using cell-cell communication modeling, we identified robust interactions between MDSCs and other cells, leading to NF-{kappa}B upregulation and an immunosuppressive microenvironment, as well as interactions involving regulatory T-cells and osteosarcoma cells that promoted tumor progression and a proangiogenic niche. Statement of SignificanceOsteosarcoma patient survival has remained stagnant for several decades due to lack of successful therapy for high-risk patients, including those with metastatic disease. Identifying novel therapeutics including immunotherapies is of great clinical importance. Our study highlights several important immunosuppressive mechanisms within osteosarcoma that should be considered when developing future immunotherapies.

cancer biology↗

bioRxiv2021

Single cell analysis of endometriosis reveals a coordinated transcriptional program driving immunotolerance and angiogenesis across eutopic and ectopic tissues.

Endometriosis is characterized by growth of endometrial-like tissue outside of the uterus affecting many women in their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, limiting diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared to matched eutopic endometrium, control endometrium, and organoids derived from these tissues, generating data on over 100,000 cells across 12 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell unique to the peritoneal lesions with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesions microenvironments, and a novel progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment representing the first comprehensive cell atlas of the disease, essential information for advancing therapeutics and diagnostics.

genomics↗

bioRxiv2020

Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

cancer biology↗