Biology subjects

Mann, K. K.

Publications and source records attributed to Mann, K. K..

5 recordsLinked to original sources

bioRxiv2024

The CCL17-CCR4 axis is critical for mutant STAT6-mediated microenvironmental remodelling and therapeutic resistance in Relapsed/Refractory Diffuse Large B Cell Lymphoma

Relapsed and refractory Diffuse Large B Cell Lymphoma (rrDLBCL) presents a significant challenge in hematology-oncology, with approximately 30-40% of DLBCL patients experiencing relapse or resistance to treatment. This underscores the urgent need to better understand the molecular mechanisms governing therapeutic resistance. Signal Transducer and Activator of Transcription 6 (STAT6) has been previously identified as a gene with recurrent D419 gain-of-function mutations in rrDLCBL. When STAT6D419 mutations are present in DLBCL tumour cells, we have demonstrated that transcription of the chemokine CCL17 (aka TARC) is increased, and tumours have increased infiltration of CD4+ T cells. However, the significance of increased T cell infiltration had not been determined. In the present study, we developed a mouse model of STAT6D419N mutant DLBCL, that recapitulates the critical features of human STAT6D419 mutant DLBCL, including increased expression of phospho-STAT6, increased CD4+ T cell invasion, and resistance to doxorubicin treatment. With this model, we found CD4+ T cells in STAT6D419N tumours have higher expression of the receptor for CCL17, CCR4. Using ex vivo functional assays we demonstrate that STAT6D419N tumour cells are directly chemoattractive to CCR4+ CD4+ T cells, and when CCR4 is inhibited using a small molecule antagonist, CD4+ T cells in STAT6D419N tumours are reduced and STAT6D419N tumours regain therapeutic sensitivity to doxorubicin. Using PhenoCycler imaging of human rrDLBCL samples, we find that STAT6D419 tumours indeed have increased expression of phospho-STAT6+ and increased cellular interactions between phospho-STAT6+ tumour cells and CD4+/ CCR4+ CD4+ T cells. Thus, our data identify CCR4 as an attractive therapeutic target in STAT6D419 mutant rrDLBCL.

cancer biology↗

bioRxiv2024

Mouse nephron formation is impaired by moderate-dose arsenical exposure

BackgroundArsenic is a naturally occurring toxicant and industrial byproduct with significant health risks. Globally, millions of people are exposed to arsenic concentrations that exceed the World Health Organizations recommended limit of 10 g/L. Chronic arsenic exposure is linked to an increased risk of chronic kidney disease (CKD); however, the effects of arsenic exposure on kidney development remain unclear. Eukaryotes methylate inorganic arsenic (iAsIII) using the enzyme arsenic 3 methyltransferase (As3mt), that converts it to methylated intermediates, mono and dimethyl arsonous acid (MMAIII and DMAIII), and mono and dimethyl arsonic acid (MMAV and DMAV). We hypothesized that arsenicals exposure during mouse kidney development impairs nephron formation. MethodsCultured mouse embryonic kidney explants were treated with inorganic arsenite (iAsIII), MMAIII, MMAV, and DMAV. Female mice harboring a humanized version of AS3MT and wild-type mice with murine As3mt were exposed to iAsIII throughout gestation and weaning and their offspring were analyzed for kidney defects. ResultsInorganic arsenic, iAsIII (200 g/L), inhibited ureteric bud branching morphogenesis and growth of mouse kidneys at embryonic day 11.5 (E11.5) and E12.5, but not at E13.5. MMAIII, but not MMAV or DMAV, impaired ureteric bud branching and kidney explant growth. Additionally, iAsIII exposure increased apoptosis in the metanephric mesenchyme of E11.5 explants and decreased Gdnf transcription, which may explain the impairment in ureteric bud branching. Humanized mouse pups exposed to 200 g/L iAsIII in utero, showed a 20% reduction in kidney weight normalized to body weight and a 28% reduction in nephron number, compared to kidneys of wild-type mice. ConclusionExposure to arsenicals during embryonic development impairs ureteric bud branching morphogenesis and decreases nephron endowment, which may predispose to CKD in adulthood.

developmental biology↗

bioRxiv2023

scCross: Bridging Modalities in Single-cell Multi-omics - Seamless Integration, Cross-modal Synthesis, and In-silico Exploration

Single-cell multi-omics illuminate intricate cellular states, yielding transformative insights into cellular dynamics and disease. Yet, while the potential of this technology is vast, the integration of its multifaceted data presents challenges. Some modalities have not reached the robustness or clarity of established scRNA-seq. Coupled with data scarcity for newer modalities and integration intricacies, these challenges limit our ability to maximize single-cell omics benefits. We introduce scCross: a tool adeptly engineered using variational autoencoder, generative adversarial network principles, and the Mutual Nearest Neighbors (MNN) technique for modality alignment. This synergy ensures seamless integration of varied single-cell multi-omics data. Beyond its foundational prowess in multi-omics data integration, scCross excels in single-cell cross-modal data generation, multi-omics data simulation, and profound in-silico cellular perturbations. Armed with these capabilities, scCross is set to transform the field of single-cell research, establishing itself in the nuanced integration, generation, and simulation of complex multi-omics data.

bioinformatics↗

bioRxiv2023

Unveiling the Impact of Arsenic Toxicity on Immune Cells in Atherosclerotic Plaques: Insights from Single-Cell Multi-Omics Profiling.

Millions worldwide are exposed to elevated levels of arsenic. This significantly increases their risk of developing atherosclerosis, a pathology primarily driven by immune cells. While the impact of arsenic on immune cell populations in atherosclerotic plaques has been broadly characterized, cellular heterogeneity is a substantial barrier to in-depth examinations of the cellular dynamics for varying immune cell populations. Here, we present one of the first single-cell multi-omics profiling of atherosclerotic plaques in apolipoprotein E knockout (apoE-/-) mice to understand the transcriptomic and epigenetic changes in various immune cells induced by arsenic. Our data reveal that arsenic alters the transcriptional profile of macrophages in a subtype-specific manner with implicated shifts in cell-cell interaction and cell fate predictions. Additionally, our data suggest that arsenic-mediated changes in chromosome accessibility are more profound than their effects on the transcriptome, hence revealing markers of arsenic exposure and potential targets of interventions. TeaserArsenic changes gene expression and epigenome primarily of macrophages in atherosclerotic plaque, suggesting intervention targets.

pharmacology and toxicology↗

bioRxiv2023

Tunable PhenoCycler Imaging of the Murine Pre-Clinical Tumour Microenvironments

The tumour microenvironment (TME) consists of tumour-supportive immune cells, endothelial cells, and fibroblasts. PhenoCycler, a high-plex single cell imaging platform, is used to characterize the complexity of the TME. Here, we used PhenoCycler to spatially resolve the TME of 8 routinely employed pre-clinical models of lymphoma, breast cancer, and melanoma. Our data reveal distinct TMEs in the different cancer models that were imaged, and show that cell-cell contacts differ depending on the tumour type examined. For instance, we found that the immune infiltration in a murine model of melanoma is altered in cellular organization in melanomas that become resistant to PD-1 therapy, with depletions in a number of cell-cell interactions. Furthermore, we provide detailed pipelines for the conjugation of antibodies that are optimized for PhenoCycler staining of murine FFPE tissues specifically, alongside open-source data analysis procedures. Overall, this is a valuable resource study seamlessly adaptable to any field of research involving murine models.

cancer biology↗