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Cancer Research
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Acute myeloid leukemia (AML) is a heterogeneous clonal disorder with a poor clinical outcome. Previously we showed that overproduction of reactive oxygen species (ROS), arising from constitutive activation of NOX2 oxidase, occurs in >60% of AML patients and that ROS production promotes proliferation of AML cells. We show here that the process most significantly affected by ROS overproduction is glycolysis. Whole metabolome analysis of 20 human primary AML showed that blasts generating high level...
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miR-223 is an anti-inflammatory microRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer (BC), we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during BC onset and progression. miR-223 expression was decreased in BC of luminal and HER2 subtypes and inversely correlated with patients9 prognosis. In normal luminal mammary epithelial cells miR-223 acted cell autonomousl...
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The dynamic interactions between an evolving malignancy and the adaptive immune system generate diverse evolutionary trajectories which ultimately result in tumor clearance or immune escape. Here, we create a simple mathematical model coupling T-cell recognition with an evolving cancer population which may randomly produce evasive subclones, imparting transient protection against the effector T-cells. T-cell turnover declines and evasion rates together explained differences in early incidence da...
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Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSCs). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that NAMPT inhibition suppresses senescence-associated CSC...
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Tumors are heterogeneous and comprised of cells with different dissemination abilities. Despite significant effort, there is no universal biological marker that serves as a metric for metastatic potential of solid tumors. Common to disseminating cells from such tumors, however, is the need to modulate their adhesion as they detach from the tumor and migrate through stroma to intravasate. Adhesion strength is heterogeneous even amongst cancer cells within a given population, and using a parallel ...
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There is a critical need to understand mechanisms of resistance and develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T-cells, and induced preferential T-cel...
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Natural killer (NK) cells are enriched within the liver. Apart from conventional NK (cNK) cells, recent studies identified a liver resident NK (LrNK) subset which constitutes about half of hepatic NK cells and exhibits distinct developmental, phenotypic and functional features. However, it remains unclear whether and how LrNK cells, as well as cNK cells, participate in the development of hepatocellular carcinoma (HCC) individually. Here, we report that both LrNK and cNK cells are significantly d...
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Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either post-formed through reciprocal signaling between tumor cells and local stromal cells or pre-formed as pre-metastatic niches before tumor cell arrival. IL-6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL-6 remain controvers...
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Mitochondria contribute to tumor growth through multiple metabolic pathways, regulation of extracellular pH, calcium signaling, and apoptosis. Using the Mitochondrial Nuclear Exchange (MNX) mouse models, which pair nuclear genomes with different mitochondrial genomes, we previously showed that mitochondrial single nucleotide polymorphisms (SNPs) regulate mammary carcinoma tumorigenicity and metastatic potential in genetic crosses. Here we tested the hypothesis that polymorphisms in stroma signif...
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Integrin β4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSCs). Immune targeting of ITGB4 represents a novel approach to target this cell population with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination, and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb) armed tumor-draining lymph node T cells. Two immunocompetent mouse models ...
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