Biology subjects

Keeley, T.

Publications and source records attributed to Keeley, T..

3 recordsLinked to original sources

bioRxiv2023

Hif-2α programmes oxygen chemosensitivity in chromaffin cells

The study of transcription factors that determine specialised neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electro-physiologically excitable cells that link the oxygen content of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by the Type I cells of the carotid body and recent work has revealed one isoform of the transcription factor HIF, HIF-2, to have a non-redundant role in the development and function of that organ. Here we show that the activation of HIF-2, including isolated overexpression alone, is sufficient to induce oxygen chemosensitivity in the otherwise unresponsive adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues that resemble the foetal organ of Zuckerkandl and also manifest oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of classes of genes that are ordinarily characteristic of the carotid body, including G-protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2 acts as a phenotypic driver for cells that display oxygen chemosensitivity, providing a route to mechanistic understanding.

developmental biology↗

bioRxiv2022

Androgen-mediated TGFβ expression suppresses anti-tumor neutrophil response in bone metastatic prostate cancer

Prostate Cancer (PCa) bone metastases are associated with spinal cord compression, fracture, bone pain and death. Despite advances in the medical therapy for localized disease, metastatic disease is incurable and osseous progression is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that tumor bone neutrophils are tumoricidal to PCa but lose their cytotoxic potential as the tumor progresses. However, there have been no studies to date to clinically define and characterize neutrophils throughout the prostate cancer disease spectrum to determine their biomarker potential. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identify that PCa progression dictates PMN properties, including viability, cell surface markers and gene expression. However, the majority of PMNs elicited an anti-tumor response ex vivo demonstrating that PMN cytotoxicity is cell autonomous and independent of PCa disease stage. In fact, we identify a novel role for androgen regulation, i.e., androgen deprivation therapy (ADT), in suppressing PMN cytotoxicity via altered transforming growth factor beta receptor I (T{beta}RI). Using preclinical models, we found that high dose testosterone/bipolar androgen therapy (BAT) and genetic or pharmacologic T{beta}RI inhibition combined with standard ADT rescued the androgen-associated suppression and restored PMN anti-tumor immune response. This combination provided a therapeutic strategy more impactful than ADT alone, in bone metastatic prostate cancer (BM-PCa). These studies: 1) highlight a necessity for both molecular and functional characterization of PMNs per cancer type and 2) reveals the ability to program PMN immune response for successful targeting of BM-PCa.

cancer biology↗

bioRxiv2022

Warming undermines emergence success in a threatened alpine stonefly: a multi-trait perspective on vulnerability to climate change

Species vulnerability to global warming is often assessed using short-term metrics such as the critical thermal maximum (CTmax), which represents an organisms ability to survive extreme heat. However, an understanding of the long-term effects of sub-lethal warming is an essential link to fitness in the wild, and these effects are not adequately captured by metrics like CTmax. The meltwater stonefly, Lednia tumana, is endemic to high-elevation streams of Glacier National Park, MT, USA, and has long been considered acutely vulnerable to climate change-associated stream warming. In 2019, it was listed as Threatened under the U.S. Endangered Species Act. This presumed vulnerability to warming was challenged by a recent study showing that nymphs can withstand short-term exposure to temperatures as high as ~27 {degrees}C. But how this short-term tolerance relates to chronic, long-term warming has remained unclear. By measuring fitness-related traits at several ecologically relevant temperatures over several weeks, we show that L. tumana cannot complete its life-cycle at temperatures well below the CTmax values measured for its nymphs. Although warmer temperatures maximized growth rates, they appear to have a detrimental impact on other key traits (survival, emergence success, and wing development), thus extending our understanding of L. tumanas vulnerability to climate change. Our results call into question the use of CTmax as a measure of thermal sensitivity, while highlighting the power and complexity of multi-trait approaches to assessing climate vulnerability.

ecology↗