Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors

Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumor progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumor-associated glycans are currently being tested in clinical trials for several tumor types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumor pathology and may pave the way for the development of new therapies for prostate cancer

The role of GCNT1 mediated O-glycosylation in aggressive prostate cancer

Prostate cancer is the most common cancer in men and a major cause of cancer related deaths worldwide. Nearly all affected men develop resistance to current therapies and there is an urgent need to develop new treatments for advanced disease. Aberrant glycosylation is a common feature of cancer cells implicated in all of the hallmarks of cancer. A major driver of aberrant glycosylation in cancer is the altered expression of glycosylation enzymes. Here, we show that GCNT1, an enzyme that plays an essential role in the formation of core 2 branched O-glycans and is crucial to the final definition of O-glycan structure, is upregulated in aggressive prostate cancer. Using in vitro and in vivo models, we show GCNT1 promotes the growth of prostate tumours and can modify the glycome of prostate cancer cells, including upregulation of core 2 O-glycans and modifying the O-glycosylation of secreted glycoproteins. Furthermore, using RNA sequencing, we find upregulation of GCNT1 in prostate cancer cells can alter oncogenic gene expression pathways important in tumour growth and metastasis. Our study highlights the important role of aberrant O-glycosylation in prostate cancer progression and provides novel insights regarding the mechanisms involved

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX-Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics

'Let the Right Ones In!': Widening Participation, Academic Writing and the Standards Debate in Higher Education

This paper challenges the frequently expressed concern, post-1992, that widening participation (WP) has contributed to a general ‘dumbing down’ of higher education in English universities *(Burke, 2005; Leathwood, 2010). In particular, it explores the implications of a long-standing ‘moral panic’ (Cohen, 1972) about the poor quality of students’ academic writing, particularly in the ‘new’ universities, which have been raised in various academic reports and countless media articles. A vampire metaphor is used throughout the paper to highlight ways in which assumptions about these falling standards in undergraduates’ academic writing feed on the foundations of a longstanding, albeit implicit, distrust of the growth in the sector on elitist, ideological grounds. The second half of the paper investigates how academic writing practices, whilst difficult to define, nonetheless wield a ‘disciplinary power’ (Foucault, 1980), over lecturers and students in the academy. This includes a discussion about how a situated, New Literacy Studies (NLS) approach to academic writing development challenges the view that students’ academic writing standards are falling. In contrast, the paper suggests that all universities have a responsibility to acknowledge and develop the different literacies that students, especially widening participation students, bring with them to university. (193

Capital transactions, disruptions and the emergence of personal capital in a lifeworld under attack

Focusing on the experiences of parents caring for their children with Batten disease this article gives an overview of Batten disease as an exemplar of a long-term disabling, degenerative condition characterised by an omnipresence of biological pathology and consequence – represented, adumbrated and organised primarily through biomedical expertise. The utility of Bourdieu's concepts of field, capital and habitus is explicated and illustrated using data from an in-depth qualitative study on Batten disease. Through applying Bourdieusian constructs, we argue that it is possible to heuristically describe a Batten field militated by the biology, with forms of capital that accord to, and represent, biomedical interest and expertise. However, we illustrate a new form of capital that develops – personal capital – borne from systematic exclusion from existing forms of capital, and the sequestration of available capital in the field by expert systems that leave parents with an acutely aware, reflexive stance rooted in responding to ‘everyday’ lifeworld. This acts as a sounding board producing new personal systems of valuation seen here as ‘personal capital’. This personal capital allows the person to reject, harness, filter and ‘trans-value’ other forms of capital in light of their immediate circumstances, and personal pursuits in the lifeworld