Biology subjects

Cooks, T.

Publications and source records attributed to Cooks, T..

5 recordsLinked to original sources

bioRxiv2026

Neuroblastoma-derived Extracellular Vesicles Disrupt the Integrity of Central Nervous System Barriers via Tight Junction Modulation

Neuroblastoma (NB) is a pediatric malignancy that predominantly affects young children and can be associated with neurological complications even in the absence of direct central nervous system (CNS) invasion. The CNS is protected by specialized endothelial barriers whose integrity depends on tightly regulated intercellular junctions and extracellular matrix homeostasis. Here, we investigated whether extracellular vesicles (EVs) released by NB cells contribute to CNS endothelial barrier dysfunction and examined the underlying molecular mechanisms.

cancer biology↗

bioRxiv2026

β-endorphin primes NK cells and NK-derived Extracellular Vesicle to enhance anti-tumor cytotoxicity

Psychoneuroimmunology suggests that positive physiological states, including laughter, could affect anti-tumor immunity, but the underlying mechanisms remain unclear. Here, we investigated whether {beta}-endorphin (BE), an endogenous opioid peptide associated with positive physiological stimuli, modulates Natural Killer (NK) cell cytotoxicity and the anti-tumor activity of NK-derived extracellular vesicles (EVs). Using NK-92 cells, we assessed cytotoxicity against JIMT1 breast cancer cells, CD107a mobilization, cytotoxic activity of conditioned medium (CM), and EV yield, cargo, and function. BE enhanced NK-92-mediated killing of JIMT1 cells without increasing CD107a mobilization, suggesting that improved cytotoxicity was not driven by classical degranulation. Consistently, CM from BE-treated NK cells retained contact-independent cytotoxicity. NK-EVs were enriched in granzyme B and perforin following BE treatment exhibiting enhanced cytotoxicity against JIMT1 and BW tumor cells. BE also increased the cytotoxic activity of primary human NK cells, and BE-conditioned NK-EVs primed naive NK-92 cells for enhanced tumor killing. These findings indicate that BE enhances NK anti-tumor immunity by remodeling the cytotoxic secretome and generating EVs that act as both direct cytotoxic effectors and mediators of NK cell priming. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=119 HEIGHT=200 SRC="FIGDIR/small/741417v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c1dfc5org.highwire.dtl.DTLVardef@14a190eorg.highwire.dtl.DTLVardef@1b32665org.highwire.dtl.DTLVardef@9db6e3_HPS_FORMAT_FIGEXP M_FIG C_FIG Proposed neuroendocrine-immune model linking positive physiological stimuli, NK cell-derived extracellular vesicles (EVs), and anti-tumor activity. Laughter is depicted as a conceptual upstream trigger of hypothalamic-pituitary signaling leading to {beta}-endorphin (BE) release. BE conditioning enhanced NK-92 cytotoxicity and the anti-tumor activity of NK-derived EVs, consistent with granzyme B and perforin enrichment and supporting EV-mediated contact-independent cancer cell killing.

cancer biology↗

bioRxiv2022

Acidovorax temperans polarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identified Acidovorax temperans as enriched in tumors. In this study, we instilled A. temperans in an animal model driven by mutant Kras and Tp53 alleles. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic genotype with increased cytokine signaling, with a global shift away from IL-1{beta} signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells which polarized to an IL-17A+ phenotype detectable in CD4+ and {gamma}{delta} populations. T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate dysbiosis promotes tumor growth by modulating inflammation.

cancer biology↗

bioRxiv2021

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+ T cells. Further activation of CD8+ T cells by supplementation with anti-programmed death-1 (PD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to PD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+ myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of PD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/PD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/457244v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c65286org.highwire.dtl.DTLVardef@1541becorg.highwire.dtl.DTLVardef@f557f3org.highwire.dtl.DTLVardef@16134dc_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cancer biology↗

bioRxiv2018

Microbiome-TP53 Gene Interaction in Human Lung Cancer

BackgroundLung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesized that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from controls (n=33) and cancer cases (n=143), we conducted 16S rRNA bacterial gene sequencing, with RNA-seq data from lung cancer cases in The Cancer Genome Atlas (n=1112) serving as the validation cohort.\n\nResultsOverall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma (SCC) specifically, a separate group of taxa were identified, in which Acidovorax was enriched in smokers (P =0.0013). Acidovorax temporans was identified by fluorescent in situ hybridization within tumor sections, and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibited higher abundance among the subset of SCC cases with TP53 mutations, an association not seen in adenocarcinomas (AD).\n\nConclusionsThe results of this comprehensive study show both a microbiome-gene and microbiome-exposure interactions in SCC lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can damage epithelial function, have a unique bacterial consortia which is higher in relative abundance in smoking-associated SCC. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

cancer biology↗