Biology subjects

Pannellini, T.

Publications and source records attributed to Pannellini, T..

5 recordsLinked to original sources

bioRxiv2023

Lymphatic Dysfunction Models an Autoimmune Emphysema Phenotype of Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease that is characterized by many clinical phenotypes. One such phenotype of COPD is defined by emphysema, pathogenic lung tertiary lymphoid organs (TLOs), and autoantibody production. We have previously shown that lymphatic dysfunction can cause lung TLO formation and lung injury in mice. We now sought to uncover whether underlying lymphatic dysfunction may be a driver of lung injury in cigarette smoke (CS)-induced COPD. We found that lung TLOs in mice with lymphatic dysfunction produce autoantibodies and are associated with a lymphatic endothelial cell subtype that expresses antigen presentation genes. Mice with underlying lymphatic dysfunction develop increased emphysema after CS exposure, with increased size and activation of TLOs. CS further increased autoantibody production in mice with lymphatic dysfunction. B-cell blockade prevented TLO formation and decreased lung injury after CS in mice with lymphatic dysfunction. Using tissue from human COPD patients, we also found evidence of a lymphatic gene signature that was specific to patients with emphysema and prominent TLOs compared to COPD patients without emphysema. Taken together, these data suggest that lymphatic dysfunction may underlie lung injury in a subset of COPD patients with an autoimmune emphysema phenotype.

pathology↗

bioRxiv2023

NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer

The clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal1. These mCRPC subtypes display increased lineage plasticity and often lack AR expression2-5. Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2)6, which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice7 recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.

cancer biology↗

bioRxiv2023

SINGLE CELL RESOLUTION SPATIAL MAPPING OF HUMAN HEMATOPOIESIS REVEALS AGING-ASSOCIATED TOPOGRAPHIC REMODELING

The spatial anatomy of hematopoiesis in bone marrow has been extensively studied in mice and other preclinical models, but technical challenges have precluded a commensurate exploration in humans. Institutional pathology archives contain thousands of paraffinized bone marrow core biopsy tissue specimens, providing a rich resource for studying the intact human bone marrow topography in a variety of physiologic states. Thus, we developed an end-to-end pipeline involving multiparameter whole tissue staining, in situ imaging at single-cell resolution, and artificial intelligence (AI)-based digital image analysis, and then applied it to a cohort of disease-free samples to survey alterations in the hematopoietic topography associated with aging. Our data indicate heterogeneity in marrow adipose tissue (MAT) content within each age group, and an inverse correlation between MAT content and proportions of early myeloid and erythroid precursors, irrespective of age. We identify consistent endosteal and perivascular positioning of hematopoietic stem and progenitor cells (HSPCs) with medullary localization of more differentiated elements and, importantly, uncover new evidence of aging-associated changes in cellular and vascular morphologies, microarchitectural alterations suggestive of inflammaging, and diminution of a potentially active megakaryocytic niche. Overall, our findings suggest that there is topographic remodeling of human hematopoiesis associated with aging. More generally, we demonstrate the potential to deeply unravel the spatial biology of normal and pathologic human bone marrow states using intact archival tissue specimens.

systems biology↗

bioRxiv2023

Distinct mesenchymal cell states mediate prostate cancer progression

Alterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for common and GEMM-specific transcriptional programs. We show that stromal responses are conserved in mouse models and human prostate cancers with the same genomic alterations. We noted striking similarities between the transcriptional profiles of the stroma of murine models of advanced disease and those of of human prostate cancer bone metastases. These profiles were then used to build a robust gene signature that can predict metastatic progression in prostate cancer patients with localized disease and is also associated with progression-free survival independent of Gleason score. Taken together, this offers new evidence that stromal microenvironment mediates prostate cancer progression, further identifying tissue-based biomarkers and potential therapeutic targets of aggressive and metastatic disease.

cancer biology↗

bioRxiv2021

Sex-specific differences in the function and differentiation of ABCsmark TLR7-driven immunopathogenesis

Sex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+ T-bet+ B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c- effector populations with pathogenic and proinflammatory potential. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.

immunology↗