Biology subjects

Sawle, A.

Publications and source records attributed to Sawle, A..

5 recordsLinked to original sources

bioRxiv2024

Tissue-resident regulatory T cells exert dualistic anti-tumour and pro-repair function in the exocrine pancreas

Regulatory T cells are fundamentally important for maintaining immune homeostasis, and their potent immune-suppressive roles make them attractive immunotherapeutic targets in cancer. Recent work suggests potential functions of tissue-resident Tregs (trTregs) in tissue-repair and epithelial cell homeostasis. Here, we describe a rare population of trTreg in the exocrine pancreas. We show that these cells share common features of trTregs, including expression of the IL-33 receptor ST2 and production of the epithelial growth factor Amphiregulin, and display an oligoclonal T cell receptor repertoire. Using a mouse model of acute pancreatitis, we show that pancreatic Tregs rapidly expand upon release of IL-33 by fibroblasts. Moreover, depletion of Tregs after initiation of pancreatic injury impairs the regeneration of the exocrine parenchyma. This effect is due, in part, through a direct effect of Tregs on acinar cell proliferation. Finally, we show that transient Treg depletion in established orthotopic pancreatic tumours leads to tumour rejection yet provokes long-lasting damages to surrounding exocrine parenchyma. In all, our results demonstrate the tissue-repair capacity of pancreatic Tregs, and highlight a dualistic role of these cells in the pancreatic tumour ecosystem, with their harmful immune-suppressive function in the tumour coupled to a beneficial tissue-repair function in the surrounding tissue.

immunology↗

bioRxiv2023

An ancient gene regulatory network sets the position of the forebrain in chordates

The evolutionary origin of the vertebrate brain is still a major subject of debate. Its distinctive dorsal position and development from a tubular neuroepithelium are unique to the chordate phylum. Conversely, apical organs (AO) are larval sensory/neurosecretory centers found in many invertebrate taxa, including in animals without a brain. Previous studies have shown that AOs are specified by a conserved set of genes under the influence of Wnt signalling. Although most of these genes are expressed in chordate nervous systems (including vertebrates), no AOs have ever been described in this group of animals. Here we have exploited single-cell genomic approaches to characterize cells showing AO profiles in sea urchin (ambulacrarian), amphioxus (invertebrate chordate) and zebrafish (vertebrate chordate). This, in combination with co-expression analysis in amphioxus embryos, has allowed us to identify an active and dynamic anterior Gene Regulatory Network (aGRN) in the three deuterostome species. We have further discovered that as well as controlling AO specification in sea urchin, this aGRN is involved in the formation of the hypothalamic region in amphioxus and zebrafish. Using a functional approach, we find that the aGRN is controlled by Wnt signalling in amphioxus, and that suppression of the aGRN by Wnt overactivation leads to a loss of forebrain cell types. The loss of the forebrain does not equate to a reduction of neuronal tissue, but to a loss of identity, suggesting a new role for Wnt in amphioxus in specifically positioning the forebrain. We thus propose that the aGRN is conserved throughout bilaterians and that in the chordate lineage was incorporated into the process of neurulation to position the brain, thereby linking the evolution of the AO to that of the chordate forebrain.

evolutionary biology↗

bioRxiv2022

Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

High grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation and CIN, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tumour tissues and 73 ovarian cancer cell lines, we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and is strongly associated with CIN and genome subclonality. Cell-based studies showed that high prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel which is the most common treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.

cancer biology↗

bioRxiv2019

ZMIZ1 - A novel Estrogen Receptor co-activator that enhances the growth of ER+ breast cancer

The Estrogen Receptor (ER) drives 75% of breast cancers. On activation, the ER recruits co-factors to form a transcriptionally active complex. These co-factors can modulate tumour growth, and understanding their roles can help to identify new therapeutic targets. Here, we present the discovery of an ER-ZMIZ1 interaction by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating that targeting ZMIZ1 results in the reduction of ER transcriptional activity at estrogen response elements and a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell-cycle genes. Integration of ENCODE data with our RNA-seq results identified ER and ZMIZ1 binding at the promoter of E2F2. We therefore propose that ER and ZMIZ1 co-regulate an important subset of cell cycle genes via a novel ER-ZMIZ1-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA, METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction ER+ patient tumours, supporting potential clinical relevance.

cancer biology↗

bioRxiv2019

Daedalus and Gasz recruit Armitage to mitochondria, bringing piRNA precursors to the biogenesis machinery

The piRNA pathway is a small RNA-based immune system that silences mobile genetic elements in animal germlines. piRNA biogenesis requires a specialised machinery that converts long single-stranded precursors into small RNAs of ~25-nucleotides in length. This process involves factors that operate in two different subcellular compartments: the nuage/Yb-body and mitochondria. How these two sites communicate to achieve accurate substrate selection and efficient processing remains unclear. Here, we investigate a previously uncharacterized piRNA biogenesis factor, Daedalus (Daed), that is located on the outer mitochondrial membrane. Daed is essential for Zucchini-mediated piRNA production and for the correct localisation of the indispensable piRNA biogenesis factor, Armitage (Armi). We find that Gasz and Daed interact with each other and likely provide a mitochondrial \"anchoring platform\" to ensure that Armi is held in place, proximal to Zucchini, during piRNA processing. Our data suggest that Armi initially identifies piRNA precursors in nuage/Yb-bodies in a manner that depends upon Piwi and then moves to mitochondria to present precursors to the mitochondrial biogenesis machinery. These results represent a significant step in understanding a critical aspect of transposon silencing, namely how RNAs are chosen to instruct the piRNA machinery in the nature of its silencing targets.

molecular biology↗