Biology subjects

Beckett, T.

Publications and source records attributed to Beckett, T..

2 recordsLinked to original sources

bioRxiv2026

Cell-type Specific Alteration of Dicer1 Accelerates Tumor Progression in Mouse Models of KRAS-driven Lung Adenocarcinoma

MicroRNAs (miRNAs) have been widely implicated in cancer initiation and progression, yet examination of the effects of global miRNA disruption on these processes has been limited. We developed novel genetically engineered mouse models of Kras-driven pulmonary adenocarcinoma (LUAD) with cell-type-specific disruption of miRNA biosynthesis via Dicer1 allele deletion, which exhibit significant differences in tumor progression rates and expected survival. Dicer1 is an RNase III enzyme that is required for the biogenesis of mature, functional miRNAs. Lung tumor progression was accelerated, and expected survival was decreased only when we initiated tumors and deleted one allele of Dicer1 in club cells and mutated Dicer1 in alveolar type 2 (AT2) cells. Reversing the cell types by inducing tumorigenesis, deleting one Dicer1 allele in AT2 cells, and mutating Dicer1 in club cells modestly accelerated tumor progression and had no effect on expected survival. Collectively, our results demonstrate that Dicer1 disruption accelerates lung cancer progression in a cell-type-dependent and non-cell-autonomous manner, and our mice represent tools for investigating the roles of miRNAs and miRNA-mediated intercellular communication in tumor progression. SummaryKras-driven mouse models show that Dicer1 mutations accelerate lung adenocarcinoma (LUAD) progression in a cell-type-dependent manner and suggest that the influence of miRNA-mediated intercellular communication is unidirectional and non-cell-autonomous.

cancer biology↗

bioRxiv2020

Prostacyclin promotes degenerative pathology in a model of Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-{beta} 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

neuroscience↗