Biology subjects

Yong, H. M.

Publications and source records attributed to Yong, H. M..

3 recordsLinked to original sources

bioRxiv2026

An Itch Receptor Drives Melanoma

Mas-Related GPCR X4 (MRGPRX4) is a sensory neuron-restricted receptor for cholestatic itch. Here, we identify MRGPRX4 as an unexpected melanoma driver. MRGPRX4 is upregulated in melanoma and is confined to invasive, neural-crest-like and pre-EMT states associated with dedifferentiation and therapy resistance. Ectopic MRGPRX4 expression in mouse melanocytes drives 100% penetrant, highly metastatic melanoma, demonstrating oncogenic behavior. MRGPRX4 promotes melanoma cell proliferation and invasion through basal, ligand-independent, PI3K-AKT-MAPK activation. Multi-omics links MRGPRX4 expression to a mesenchymal/neural-crest-like program that defines a distinct invasive MRGPRX4? niche. Comparing transcptomics of MRGPRX4-driven tumors shows a broad overlap with BRAF/NRAS-driven tumors; however, the MRGPRX4 model also enriches an ECM-rich, invasive neural crest-like melanoma state. MRGPRX4 further remodels the tumor microenvironment toward an immunosuppressive, checkpoint-high state enriched in suppressive myeloid cells. Pharmacologic MRGPRX4 inhibition suppresses basal signaling and limits melanoma growth and invasion. In sum, melanoma exploits MRGPRX4 to acquire an invasive and immunosuppressive phenotype, nominating this somatosensory GPCR as a promising therapeutic target.

cancer biology↗

bioRxiv2024

Air pollution drives macrophage senescence through a phagolysosome-15-lipoxygenase pathway

Urban particulate matter (uPM) poses significant health risks, particularly to the respiratory system. Fine particles, such as PM2.5, can penetrate deep into the lungs and exacerbate a range of health problems, including emphysema, asthma, and lung cancer. PM exposure is also linked to extra-pulmonary disorders like heart and neurodegenerative diseases. Moreover, prolonged exposure to elevated PM levels can reduce overall life expectancy. Senescence is a dysfunctional cell state typically associated with age but can also be precipitated by environmental stressors. This study aimed to determine whether uPM could drive senescence in macrophages, an essential cell type involved in particulate phagocytosis-mediated clearance. While it is known that uPM exposure impairs immune function, this deficit is multi-faceted and incompletely understood, partly due to the use of particulates such as diesel exhaust particle (DEP) as a surrogate for true uPM. uPM was collected from several locations in the USA, including Baltimore, Houston, and Phoenix. Bone marrow-derived macrophages (BMDMs) were stimulated with uPM or reference particulates (e.g., DEP) to assess senescence-related parameters. We report that uPM-exposed BMDMs adopt a senescent phenotype characterized by increased IL-1 secretion, senescence- associated {beta}-galactosidase activity, and diminished proliferation. Exposure to allergens failed to elicit such a response, supporting a distinction between different types of environmental exposures. uPM-induced senescence was independent of key macrophage activation pathways, specifically inflammasome and scavenger receptor. However, inhibition of the phagolysosome pathway abrogated senescence markers, supporting this phenotypes attribution to uPM phagocytosis. These data suggest uPM exposure leads to macrophage senescence, which may contribute to immunopathology.

immunology↗

bioRxiv2020

Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

Allergic diseases arise in susceptible individuals in part because of decrements in protective pathways. The mechanism by which these anti-inflammatory molecules become repressed remains unclear. We have previously reported that epithelial dectin-1 prevents aberrant type 2 responses and is downregulated in the epithelium of allergic patients. Here we report that dectin-1 is constitutively expressed by the respiratory epithelium in humans, and that IL-33 specifically acts as a repressor of dectin-1. Mechanistically, this occurs via IL-33-dependent STAT3 activation and the subsequent repression of the dectin-1 gene, CLEC7A. We have identified a novel enhancer region upstream of the proximal promoter of CLEC7A that is only accessible in epithelial cells, but not in hematopoietic cells. Epigenetic repression of CLEC7A through this newly identified locus, downstream of an aberrant IL-33-STAT3 axis, occurs in the epithelium of allergic individuals. Collectively, our data identify a mechanism of epigenetic fine-tuning of dectin-1 expression in epithelial cells that may participate in allergenicity.

immunology↗