Browsing by Author "Kucera, Gregory L."

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    c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities
    (MDPI, 2023-05-05) Liu, Yin; Smith, Margaret R.; Wang, Yuezhu; D’Agostino, Ralph, Jr.; Ruiz, Jimmy; Lycan, Thomas; Kucera, Gregory L.; Miller, Lance D.; Li, Wencheng; Chan, Michael D.; Farris, Michael; Su, Jing; Song, Qianqian; Zhao, Dawen; Chandrasekaran, Arvind; Xing, Fei; Biostatistics and Health Data Science, School of Medicine
    The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.
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    Modulation of oxidative phosphorylation and mitochondrial biogenesis by cigarette smoke influence the response to immune therapy in NSCLC patients
    (Elsevier, 2023-04) Wang, Yuezhu; Smith, Margaret; Ruiz, Jimmy; Liu, Yin; Kucera, Gregory L.; Topaloglu, Umit; Chan, Michael D.; Li, Wencheng; Su, Jing; Xing, Fei; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint blockade (ICB). However, only a subset of patients experience benefit after receiving ICBs. Therefore, it is of paramount importance to increase the response rate by elucidating the underlying molecular mechanisms and identifying novel therapeutic targets to enhance the efficacy of IBCs in non-responders. We analyzed the progression-free survival (PFS) and overall survival (OS) of 295 NSCLC patients who received anti-PD-1 therapy by segregating them with multiple clinical factors including sex, age, race, smoking history, BMI, tumor grade and subtype. We also identified key signaling pathways and mutations that are enriched in patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. We found that former and current smokers have a higher response rate to anti-PD-1 treatment than non-smokers. GSEA results revealed that oxidative phosphorylation (OXPHOS) and mitochondrial related pathways are significantly enriched in both responders and smokers, suggesting a potential role of cellular metabolism in regulating immune response to ICB. We also demonstrated that all-trans retinoic acid (ATRA) which enhances mitochondrial function significantly enhanced the efficacy of anti-PD-1 treatment in vivo. Our clinical and bioinformatics based analyses revealed a connection between smoking induced metabolic switch and the response to immunotherapy, which can be the basis for developing novel combination therapies that are beneficial to never smoked NSCLC patients.