Biology subjects

Basham, K. J.

Publications and source records attributed to Basham, K. J..

5 recordsLinked to original sources

bioRxiv2024

Single-cell analysis of human airway epithelium identifies cell type-specific responses to Aspergillus and Coccidioides

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii. To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii, providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways. ImportanceFungal infections in the lungs are dreaded complications for those with compromised immune systems and have limited treatment strategies available. These options are restricted further by the increased prevalence of treatment-resistant fungi. Many studies focus on how our immune systems respond to these pathogens, yet airway epithelial cells remain an understudied component of fungal infections in the lungs. Here, the authors provide a transcriptional analysis of primary human airway epithelial cells stimulated by two distinct fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii. These data will enable further mechanistic studies of the contribution of the airway epithelium to initial host responses and represent a powerful new resource for investigators.

immunology↗

bioRxiv2024

Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production

The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications. HighlightsO_LIWNT2B variant is associated with increased risk for primary aldosteronism C_LIO_LIWnt2b knock-out mice show defects in adrenal morphology C_LIO_LIWnt2b knock-out mice have hyperreninemic hypoaldosteronism C_LIO_LIWNT2B activates non-canonical Wnt/planar cell polarity signaling C_LIO_LIWNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism C_LI

genetics↗

bioRxiv2023

Cross-kingdom anti-inflammatory effects of fungal melanin on airway epithelium by post-translational blockade of chemokine secretion

Respiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

immunology↗

bioRxiv2022

Targeting oncogenic Wnt/β-catenin signaling in adrenocortical carcinoma disrupts ECM expression and impairs tumor growth.

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer with limited treatment options and poor survival for patients with advanced disease. Improved understanding of transcriptional programs engaged in ACC will help direct rational, targeted therapies. While activating mutations in Wnt/{beta}-catenin signaling are frequently observed, the {beta}-catenin-dependent transcriptional targets that promote tumor progression are poorly understood. To address this question, we used independent component analysis and identified a novel Wnt/{beta}-catenin-associated signature in ACC predictive of poor survival. This signature was enriched for the extracellular matrix (ECM), suggesting a potential role for Wnt/{beta}-catenin in regulating the ACC microenvironment. We further investigated the minor fibrillar collagen, collagen XI alpha 1 (COL11A1), and found that COL11A1 expression strongly correlated with both Wnt/{beta}-catenin activation and poor patient survival. Inhibition of constitutively active Wnt/{beta}-catenin signaling in the human ACC cell line, NCI-H295R, significantly reduced expression of COL11A1 and other ECM components, and decreased viability of cancer cells in vitro. To investigate the preclinical potential of Wnt/{beta}-catenin inhibition in vivo, we developed and characterized a novel orthotopic xenograft model utilizing minimally invasive techniques. Treatment with the newly developed Wnt/{beta}-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth in this preclinical model. Together, our data supports that inhibition of aberrantly active Wnt/{beta}-catenin disrupts transcriptional reprogramming of the microenvironment and reduces ACC growth and survival. Furthermore, this {beta}-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/{beta}-catenin inhibitor. These results show promise for further clinical development of Wnt/{beta}-catenin inhibitors in ACC and unveil a novel Wnt/{beta}-catenin-regulated transcriptome. Simple SummaryAdrenocortical carcinoma (ACC) is a rare, often deadly cancer arising from the adrenal gland. Mortality associated with ACC remains unchanged over the last several decades. The rarity of ACC, an incomplete understanding of its molecular basis, and limited availability of pre-clinical models have hampered the development of new effective therapies. The present work aims to address these gaps with a focus on the Wnt/{beta}-catenin cell signaling pathway, which is aberrantly activated in ~40% of ACC tumors. We discover a novel ECM program activated in ACC that is associated with Wnt/{beta}-catenin and poor survival. Wnt/{beta}-catenin inhibition disrupts expression of ECM genes and induces loss of cancer cell viability. To extend these findings, we develop a rapid orthotopic mouse model of ACC and demonstrate that disruption of the Wnt/{beta}-catenin axis with novel small molecule inhibitor Tegavivint is a potential effective therapeutic strategy to reduce ACC tumor burden in vivo.

cancer biology↗

bioRxiv2022

Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner

Aging is a carcinogen that markedly increases cancer risk, yet we have limited mechanistic understanding of cancer initiation in aged cells. Here, we demonstrate induction of the hallmark aging process cellular senescence, triggered by loss of Wnt inhibitor ZNRF3, remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer. Detailed characterization reveals a striking sexual dimorphism. Males exhibit earlier senescence activation and a greater innate immune response. This results in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and are more prone to metastatic cancer. Senescence-recruited myeloid cells become increasingly depleted with advanced tumor progression, which is recapitulated in patients where a low myeloid signature is associated with worse outcome. Collectively, our study reveals a novel role for myeloid cells in restraining adrenal cancer progression with significant prognostic value, and provides a model for interrogating pleiotropic effects of cellular senescence in cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/488426v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@bddf22org.highwire.dtl.DTLVardef@18434a3org.highwire.dtl.DTLVardef@9bc772org.highwire.dtl.DTLVardef@1430fbb_HPS_FORMAT_FIGEXP M_FIG Graphical abstract created with BioRender.com C_FIG

cancer biology↗