Biology subjects

Hutton, E.

Publications and source records attributed to Hutton, E..

6 recordsLinked to original sources

bioRxiv2026

Characterisation of prostate cancer sialome re-engineering via CMAH transfection reveals a bystander effect that propagates Neu5Gc presentation to neighbouring cells

Sialic acids are a family of nine-carbon -keto sugars that play essential roles in human health and disease. In mammals, they are found in two main forms: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), with interactions between Neu5Ac-containing glycans and Siglec receptors on immune cells increasingly recognised as glyco-immune checkpoints, promoting immunosuppression. However, humans do not synthesise Neu5Gc due pseudogenisation of the CMAH gene which encodes the cytidine monophospho-N-acetylneuraminic acid hydroxylase enzyme responsible for CMP-Neu5Ac conversion into CMP-Neu5Gc, which then serves as the donor substrate for sialyltransferases. Here, we investigated the effects of re-engineering tumour cell-surface glycans in a prostate cancer cell model by expressing rat CMAH, thereby enabling the conversion of CMP-Neu5Ac to CMP-Neu5Gc. LNCaP cells transfected with the rat CMAH gene predominantly incorporated Neu5Gc into mucin-associated O-glycans implicated in immune suppression. Treatment with sialidase significantly reduced Neu5Gc expression, indicating that Neu5Gc was presented on cell-surface glycans, while cell-tracing experiments demonstrated the transfer of Neu5Gc to neighbouring cells, revealing a potential bystander effect capable of propagating Neu5Gc expression within the tumour microenvironment.

cancer biology↗

bioRxiv2025

The Androgen Receptor and MYC synergise to modulate the synthesis of Siglec-7 ligands in prostate cancer

Glyco-immune checkpoints have recently been shown to be critical mediators of immunotherapy resistance across multiple cancer types. In clinical trials, immunotherapeutic treatments for prostate cancer have failed to elicit durable clinical responses. PCa progression is driven by transcriptional networks regulated by key transcription factors including the androgen receptor (AR) and the oncogene MYC. How this crossover between hormone and oncogene-driven signalling pathways regulates tumour glyco-immune checkpoints remains unclear. Here, we show that O-glycans are the major substrates for sialylation in prostate cancer and that sialyltransferases that have preferences for O-glycans are differentially regulated by androgens. We show that supraphysiological levels of androgens produce distinct glycopeptide profiles in prostate cancer cells compared with cells exposed to physiological androgens. Additionally, we identify a direct and coordinated role for AR and MYC in regulating ST3Gal1 and the synthesis of Siglec-7 ligands in prostate cancer. Both transcription factors converge to repress ST3GAL1, thereby limiting the generation of Siglec-7 ligands. These findings highlight a context-dependent, cooperative relationship between the AR and MYC in shaping the tumour sialome, linking hormonal signalling and oncogenic transcription to Siglec biology. Our study highlights how cell-type specific differences in transcriptional networks has important downstream effects for immune modulating glycans and has tumour specific clinical implications.

cancer biology↗

bioRxiv2023

Oncogenic RAS drives rapid onset cellular plasticity and elicits a tumour-promoting neutrophil response at the inception of preneoplastic development

Oncogenic driver mutations are frequently found in normal tissues, suggesting that additional non-genetic factors are required for tumourigenesis. Phenotypic plasticity is an important gateway to malignancy and inflammation can fuel tumourigenesis, however, little is known about when and how these hallmarks first arise. Using single-cell transcriptomics and in vivo live imaging we have characterised the immediate cell intrinsic and innate immune responses during the first 24 hours following oncogenic Ras activation, in an inducible zebrafish model of HRASG12V-mediated skin tumour initiation. We found that only a subset of basal keratinocytes, but not superficial keratinocytes, are susceptible to RAS-driven phenotypic plasticity. These preneoplastic cells undergo dedifferentiation and partial EMT, resembling malignant cells observed in human squamous cell carcinoma (SCC). Strikingly, the same subset instigates the development of tumour-promoting neutrophils, which in turn enhance preneoplastic cell proliferation. Our findings demonstrate that the effects of oncogenic Ras are primarily determined by the cell of origin and reveal an association between the unlocking of phenotypic plasticity and the onset of tumour-promoting inflammation.

cancer biology↗

bioRxiv2019

ACE: A Probabilistic Model for Characterizing Gene-Level Essentiality in CRISPR Screens

High-throughput knockout screens based on CRISPR-Cas9 are widely used to evaluate the essentiality of genes across a range of cell types. Here we introduce a probabilistic modeling framework, Analysis of CRISPR-based Essentiality (ACE), that enables new statistical tests for essentiality based on the raw sequence read counts from such screens. ACE estimates the essentiality of each gene using a flexible likelihood framework that accounts for multiple sources of variation in the CRISPR-Cas9 experimental process. In addition, the method can identify genes that differ in their degree of essentiality across samples using a likelihood ratio test. We show using simulations that ACE is competitive with the best available methods in predicting essentiality, and is especially useful for the identification of differential essentiality. Furthermore, by applying ACE to publicly available CRISPR-screen data, we are able to identify both known and previously overlooked candidates for genotype-specific essentiality, including RNA m6-A methyltransferases that exhibit enhanced essentiality in the presence of inactivating TP53 mutations. In summary, ACE provides improved quantification of essentiality specific to cancer subtypes, and a robust probabilistic framework for identifying genes responsive to therapeutic targeting.

bioinformatics↗

bioRxiv2019

Sexual dichromatism in the neotropical genus Mannophryne (Anura: Aromobatidae)

Recent reviews on sexual dichromatism in frogs included Mannophryne trinitatis as the only example they could find of dynamic dichromatism (males turn black when calling) within the family Aromobatidae and found no example of ontogenetic dichromatism in this group. We demonstrate ontogenetic dichromatism in M. trinitatis by rearing post-metamorphic froglets to near maturity: the throats of all individuals started as grey coloured; at around seven weeks, the throat became pale yellow in some, and more strongly yellow as development proceeded; the throats of adults are grey in males and variably bright yellow in females, backed by a dark collar. We demonstrated the degree of throat colour variability by analysing a large sample of females. The red: green (R:G) ratio ranged from ~1.1 to 1.4, reflecting variation from yellow to yellow/orange, and there was also variation in the tone and width of the dark collar, and in the extent to which the yellow colouration occurred posterior to the collar. Female M. trinitatis are known to be territorial in behaviour. We show a positive relationship between throat colour (R:G ratio) and escape performance, as a proxy for quality. Our field observations on Tobagos M. olmonae showed variability in female throat colour and confirmed that males in this species also turn black when calling. Our literature review of the 20 Mannophryne species so far named showed that all females have yellow throats with dark collars, and that male colour change to black when calling has been reported in eight species; in the remaining 12 species, descriptions of males calling are usually lacking so far. We predict that both dynamic and ontogenetic sexual dichromatism are universal in this genus and provide discussion of the ecological role of dichromatism in this genus of predominantly diurnal, non-toxic frogs, with strong paternal care of offspring.

zoology↗

bioRxiv2017

Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line

The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences, and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available with nearly 20,000 variants present, most of which were missed by prior efforts. Surrounding the important HER2 locus, we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the transcriptome and sheds new light on the complexity of cancer progression.

genomics↗