Browsing by Author "Wang, Qingfei"
Now showing 1 - 10 of 10
Results Per Page
Sort Options
Item CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10(Cell Press, 2020) Guldner, Ian H.; Wang, Qingfei; Yang, Lin; Golomb, Samantha M.; Zhao, Zhuo; Lopez, Jacqueline A.; Brunory, Abigail; Howe, Erin N.; Zhang, Yizhe; Palakurthi, Bhavana; Barron, Martin; Gao, Hongyu; Xuei, Xiaoling; Liu, Yunlong; Li, Jun; Chen, Danny Z.; Landreth, Gary E.; Zhang, Siyuan; Medical and Molecular Genetics, School of MedicineBrain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response during br-met outgrowth. We found Ccr2+ BMDMs minimally influenced br-met while CNS-myeloid promoted br-met outgrowth. Additionally, br-met-associated CNS-myeloid exhibited downregulation of Cx3cr1. Cx3cr1 knockout in CNS-myeloid increased br-met incidence, leading to an enriched interferon response signature and Cxcl10 upregulation. Significantly, neutralization of Cxcl10 reduced br-met, while rCxcl10 increased br-met and recruited VISTAHi PD-L1+ CNS-myeloid to br-met lesions. Inhibiting VISTA- and PD-L1-signaling relieved immune suppression and reduced br-met burden. Our results demonstrate that loss of Cx3cr1 in CNS-myeloid triggers a Cxcl10-mediated vicious cycle, cultivating a br-met-promoting, immune-suppressive niche.Item Increased PIEZO1 Expression Is Associated with Worse Clinical Outcomes in Hormone-Receptor-Negative Breast Cancer Patients(MDPI, 2024-02-06) Poole, Rylee Ann; Wang, Qingfei; Ray, Alo; Takabe, Kazuaki; Opyrchal, Mateusz; Katsuta, Eriko; Medicine, School of MedicinePIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. An analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis. We also analyzed the immune cell composition in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that the PIEZO1 expression levels are higher in hormone-receptor (HR)-negative than in HR-positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR-negative cohorts, especially in triple-negative breast cancer (TNBC), suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR-negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high-PIEZO1 HR-negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high-PIEZO1 HR-negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR-negative breast cancer.Item Isolation of mouse brain-infiltrating leukocytes for single cell profiling of epitopes and transcriptomes(Elsevier, 2021-05-13) Guldner, Ian H.; Golomb, Samantha M.; Wang, Qingfei; Wang, Emilia; Zhang, Siyuan; Medicine, School of MedicineHigh dimensional compositional and transcriptional profiling of heterogeneous brain-infiltrating leukocytes can lead to novel biological and therapeutic discoveries. High-quality single-cell leukocyte preparations are a prerequisite for optimal single cell profiling. Here, we describe a protocol for epitope and RNA-preserving dissociation of adult mouse brains and subsequent leukocyte purification and staining, which is adaptable to homeostatic and pathogenic brains. Leukocyte preparation following this protocol permits exquisite single-cell surface protein and RNA profiling in applications including CyTOF and CITE-seq. For complete details on the use and execution of this protocol, please refer to Guldner et al. (2020) and Golomb et al. (2020).Item Mechano-Sensing Channel PIEZO2 Enhances Invasive Phenotype in Triple-Negative Breast Cancer(MDPI, 2022-08-31) Katsuta, Eriko; Takabe, Kazuaki; Vujcic, Marija; Gottlieb, Philip A.; Dai, Tao; Mercado-Perez, Arnaldo; Beyder, Arthur; Wang, Qingfei; Opyrchal, Mateusz; Medicine, School of MedicineBackground: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca2+ channels, and cell depolarization. This study aimed to investigate PIEZO2’s role in breast cancer. Methods: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. Results: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial–mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. Conclusion: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients.Item Multi-modal Single-Cell Analysis Reveals Brain Immune Landscape Plasticity during Aging and Gut Microbiota Dysbiosis(Elsevier, 2020-12-01) Golomb, Samantha M.; Guldner, Ian H.; Zhao, Anqi; Wang, Qingfei; Palakurthi, Bhavana; Aleksandrovic, Emilija A.; Lopez, Jacqueline A.; Lee, Shaun W.; Yang, Kai; Zhang, Siyuan; Medicine, School of MedicinePhenotypic and functional plasticity of brain immune cells contribute to brain tissue homeostasis and disease. Immune cell plasticity is profoundly influenced by tissue microenvironment cues and systemic factors. Aging and gut microbiota dysbiosis that reshape brain immune cell plasticity and homeostasis has not been fully delineated. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we analyze compositional and transcriptional changes of the brain immune landscape in response to aging and gut dysbiosis. Discordance between canonical surface-marker-defined immune cell types and their transcriptomes suggest transcriptional plasticity among immune cells. Ly6C+ monocytes predominate a pro-inflammatory signature in the aged brain, while innate lymphoid cells (ILCs) shift toward an ILC2-like profile. Aging increases ILC-like cells expressing a T memory stemness (Tscm) signature, which is reduced through antibiotics-induced gut dysbiosis. Systemic changes due to aging and gut dysbiosis increase propensity for neuroinflammation, providing insights into gut dysbiosis in age-related neurological diseases.Item Neutrophils Resist Ferroptosis and Promote Breast Cancer Metastasis through Aconitate Decarboxylase 1(Elsevier, 2023) Zhao, Yun; Liu, Zhongshun; Liu, Guoqiang; Zhang, Yuting; Liu, Sheng; Gan, Dailin; Chang, Wennan; Peng, Xiaoxia; Sung, Eun Suh; Gilbert, Keegan; Zhu, Yini; Wang, Xuechun; Zeng, Ziyu; Baldwin, Hope; Ren, Guanzhu; Weaver, Jessica; Huron, Anna; Mayberry, Toni; Wang, Qingfei; Wang, Yujue; Diaz-Rubio, Maria Elena; Su, Xiaoyang; Stack, M. Sharon; Zhang, Siyuan; Lu, Xuemin; Sheldon, Ryan D.; Li, Jun; Zhang, Chi; Wan, Jun; Lu, Xin; Medical and Molecular Genetics, School of MedicineMetastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.Item Petrogenesis of Early Cretaceous intermediate-felsic dikes in the Jiaodong Peninsula, south-eastern North China Craton: Constraints from geochronology, geochemistry and Sr-Nd-Pb-Hf isotopes(Elsevier, 2018-08) Liu, Xuefei; Deng, Jun; Liang, Yayun; Wang, Qingfei; Pan, Ruiguang; Qin, Cheng; Yang, Yi; Earth Sciences, School of ScienceEarly Cretaceous dike swarms are widely developed in the Jiaodong Peninsula, NE China. In this study, we newly investigated the spatial-temporal distribution, petrography, geochronology and whole-rock geochemistry of the intermediate-felsic dikes from the Jiaobei terrane and the Sulu orogenic belt in the Jiadong Peninsula. The zircon U-Pb dating has constrained the timing of the emplacement of intermediate-felsic dikes to 128–108 Ma. The quartz diorite dikes in Jiaobei show adakitic geochemical features, including high SiO2 (66.3–67.5 wt%) contents and high Sr/Y (76–149) and La/Yb (41–91) ratios. The combination of a series of isotopic data, including initial 87Sr/86Sr ratios (0.7098–0.7104) and negative εNd(t) (−20.1 to −14.7) and zircon εHf(t) values (−19.9 to −9.5), indicates that these quartz diorite dikes were likely derived from partial melting of thickened ancient lower crust with involvement of underplated mafic magmas. Additionally, the diorite dikes in Jiaobei and those in Sulu show similar chemical compositions, as both yield the high-Mg andesite (or andesitic rocks) (HMAs) characteristics with a high Mg# value (60–72), high MgO, Cr, and Ni contents, and low Na2O (average = 3.25 wt%) contents. They also exhibit crustal geochemical signatures, such as depletion in Nb, Ta, and Ti, but enrichment in Th and U; high initial 87Sr/86Sr ratios (0.7063–0.7094), and low εNd(t) (−16.7 to −9.6) and εHf(t) values (−29.4 to −9.8). The entire geochemical evidences imply that they derived from the partial melting of mantle wedge peridotite metasomatized by hydrous fluids from the subduction of the oceanic slab with marine sediments. In combination with the Early Cretaceous intrusions and mafic dikes at Jiaodong, the intermediate-felsic dikes represent a magmatic response to lithospheric thinning resulted from the prolonged thermo-mechanical-chemical erosion processes caused by slab rollback of the Paleo-Pacific plate.Item Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer(Springer Nature, 2019-08-23) Wang, Qingfei; Guldner, Ian H.; Golomb, Samantha M.; Sun, Longhua; Harris, Jack A.; Lu, Xin; Zhang, Siyuan; Medicine, School of MedicineAcquired resistance to targeted cancer therapy is a significant clinical challenge. In parallel with clinical trials combining CDK4/6 inhibitors to treat HER2+ breast cancer, we sought to prospectively model tumor evolution in response to this regimen in vivo and identify a clinically actionable strategy to combat drug resistance. Despite a promising initial response, acquired resistance emerges rapidly to the combination of anti-HER2/neu antibody and CDK4/6 inhibitor Palbociclib. Using high-throughput single-cell profiling over the course of treatments, we reveal a distinct immunosuppressive immature myeloid cell (IMC) population to infiltrate the resistant tumors. Guided by single-cell transcriptome analysis, we demonstrate that combination of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockade enhances anti-tumor immunity, and overcomes the resistance. Furthermore, sequential combinatorial immunotherapy enables a sustained control of the fast-evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses.Item Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer(Springer Nature, 2023-04-13) Palakurthi, Bhavana; Fross, Shaneann R.; Guldner, Ian H.; Aleksandrovic, Emilija; Liu, Xiyu; Martino, Anna K.; Wang, Qingfei; Neff, Ryan A.; Golomb, Samantha M.; Lewis, Cheryl; Peng, Yan; Howe, Erin N.; Zhang, Siyuan; Biochemistry and Molecular Biology, School of MedicineChemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.Item Understanding and targeting erythroid progenitor cells for effective cancer therapy(Wolters Kluwer, 2023) Wang, Qingfei; Poole, Rylee A.; Opyrchal, Mateus; Medicine, School of MedicinePurpose of review: It is well described that tumor-directed aberrant myelopoiesis contributes to the generation of various myeloid populations with tumor-promoting properties. A growing number of recent studies have revealed the importance of the previously unappreciated roles of erythroid progenitor cells (EPCs) in the context of cancer, bringing the updated concept that altered erythropoiesis also facilitates tumor growth and progression. Better characterization of EPCs may provide attractive therapeutic opportunities. Recent findings: EPCs represent a heterogeneous population. They exhibit crucial pro-tumor activities by secreting growth factors and modulating the immune response. Cancers induce potent EPC expansion and suppress their differentiation. Recent single-cell transcriptome and lineage tracking analyses have provided novel insight that tumor-induced EPCs are able to be transdifferentiated into immunosuppressive myeloid cells to limit T-cell function and immunotherapy. Therapeutic strategies targeting key factors of EPC-driven immunosuppression, reducing the amount of EPCs, and promoting EPC differentiation and maturation have been extensively investigated. Summary: This review summarizes the current state of knowledge as to the fascinating biology of EPCs, highlights mechanisms by which they exert the tumor promoting activities, as well as the perspectives on future directions and strategies to target these cells for potential therapeutic benefit.