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Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation

ABSTRACT: Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post59 translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy66 induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome deglycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160205 | GEO | 2023/04/05

REPOSITORIES: GEO

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Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation

Project description:Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome deglycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance

2023-04-05 | PXD022240 | Pride

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. Interestingly, IFNγ functions by stimulating the expression of T cell killing-related molecules in a cell type-specific manner. Additionally, by assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a novel and critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Moreover, proper fucosylation of CD123 is required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T cell engaging CD3-bispecific antibody therapies.

2020-11-12 | GSE159547 | GEO

Effects of fucosylation inhibitors on ATRA differentiation in myeloid leukemia cells

Project description:Differentiation therapy with all-trans retinoic acid (ATRA) is well established for acute promyelocytic leukemia (APL). However, the narrow application and tolerance development of ATRA remain to be improved. In this study, we challenged glycosylation inhibitor to obtain better efficiency than ATRA alone. As a result, we found that the combination of fucosylation inhibitor 6-alkynylfucose (6AF) with ATRA have profound effect for differentiation, shown by expression changes of differentiation markers CD11b, CD11c, with significant morphological change in NB4 and HL-60 cells. From lectin blot assay, we found that ATRA or 6AF alone could decrease core fucosylation, the combination of these two agents efficiently decreases the expression of core fucosylation. To reveal molecular mechanisms to reveal 6AF effect for ATRA induced differentiation, we next performed microarray analysis using NB4 cells. From pathway analysis using DAVID software, we found that C-type lectin receptor (CLR) signaling pathway was enriched as high significance. From real time PCR analysis, using NB4 and HL-60 cells, FcRI, CLEC6A, CASP1, IL-1, EGR2/3, the components of CLR, and Akt, were indeed upregulated by 6AF in ATRA induced differentiation. These suggest that the involvement of CLR signaling pathway in 6AF effect of ATRA induced differentiation.

2023-06-08 | GSE234103 | GEO

Core fucosylation in mesenchymal glioblastoma

Project description:Glycoproteomic screening indicates that core fucosylation activation is more highly enhancedin mesenchymal (MES) than in proneural (PN) glioblastoma cancer stem cells (GSCs) and this pattern is retained in subgroup-specific xenograftsand human patients’ samples. Most MES-restricted core fucosylated proteins are involved in therapeutically relevant pathological processes, such as extracellular matrix interaction and tumor invasion.

2022-11-09 | PXD033408 | Pride

Rapidly induced fucosylation of intestinal epithelium sustains host-commensal symbiosis during sickness.

Project description:Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Among these responses, temporary anorexia associated with an infection is often beneficial. It poses, however, a problem for the trillions of microbes residing in the gastrointestinal tract, as they also experience reduced substrate availability. We hypothesized that under anorectic conditions caused by infection, the host might activate protective mechanisms to support the gut microbiota during the acute phase of the disease. Here, we report that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α1,2-fucosylation of the small intestine epithelial cells (IEC). The process requires sensing of TLR agonists and production of IL-23 by dendritic cells, activation of innate lymphoid cells and expression of α1,2-Fucosyltransferase-2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is utilized by microbiota, as shown using reporter bacteria and by transcriptional profiling of the gut microbiome. Fucosylation also reduces the expression of bacterial virulence genes within the commensal gut microbiome and improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host-microbial interactions during pathogen-induced stress. RNA-Seq analysis of the murine gut microbiome following LPS exposure. Fut2-/- (B6.129X1-Fut2tm1Sdo/J) mice were backcrossed greater than 7 generations to BALB/c. Fut2-/- (KO) and Fut2+/- (Het) animals were analyzed.

2014-10-24 | E-GEOD-60874 | biostudies-arrayexpress

Aberrant L-Fucose accumulation and increased core fucosylation are specific metabolic liabilities in mesenchymal glioblastoma

Project description:Dysregulated metabolism in glioblastoma (GBM), the deadliest brain tumor of adults, offers an opportunity to deploy metabolic interventions as precise therapeutic strategies. To identify the molecular drivers and the modalities by which different molecular subgroups of GBM exploit metabolic rewiring to sustain tumor progression, we interrogated the transcriptome, the metabolome and the glycoproteome of human subgroup-specific GBM stem cells (GSCs). Here we report that L-Fucose abundance and core fucosylation activation are more highly enhanced in mesenchymal (MES) than in proneural (PN) GSCs; this pattern is retained in subgroup-specific xenografts and, most significantly, retrieved in subgroup-affiliated human patients’ samples. Genetic and pharmacological inhibition of core fucosylation in MES GBM preclinical models results in significant reduction in tumor burden. LC/MS-based glycoproteomic screening indicates that most MES-restricted core fucosylated proteins are involved in therapeutically relevant GBM pathological processes, such as extracellular matrix interaction, cell adhesion and integrin-mediated signaling. Notably, selective L-Fucose accumulation in MES GBMs is demonstrated by pre-clinical minimally-invasive positron emission tomography (PET), implying this metabolite as a potential subgroup-restricted biomarker. Overall, these findings indicate that L-Fucose pathway activation in MES GBM offers subgroup-specific, GSC-restricted dependencies to be exploited as diagnostic markers and actionable therapeutic targets.

2022-11-08 | GSE202200 | GEO

Rapidly induced fucosylation of intestinal epithelium sustains host-commensal symbiosis during sickness.

2014-10-24 | GSE60874 | GEO

Core fucosylation of IL-15 receptor delineates homeostatic proliferation and apoptosis signalling required for natural killer cell development

Project description:Natural Killer (NK) cell development and effector function requires context-dependent signalling via numerous receptors including the IL-15 receptor. The modulation of receptor signalling can be regulated by the post-translational modifications affecting receptor turnover and trafficking. Core fucosylation is one such modification known to impact receptor expression and is uniquely mediated by fucosyltransferase 8 (FUT8). To investigate core fucosylation in NK cell biology, we generated mice lacking FUT8 in NK cells (Fut8fl/flNcr1cre/+). Loss of core fucose resulted in pronounced NK lymphopenia in Fut8fl/flNcr1cre/+ mice associated with a reduction in IL-15 receptor expression and loss of in vivo proliferation. Inhibition of intrinsic apoptosis pathways could not overcome compromised IL-15 receptor signalling to rescue FUT8-null NK cell development delineating the contribution of proliferation to NK cell homeostasis. Surprisingly, loss of core fucose enhanced NK cell expansion following viral infection and this was associated with upregulation of IL-2Rα following pro-inflammatory cytokine exposure and enhanced IL-2-mediated proliferation. Lastly, loss of FUT8 activity impaired TGFBR2 expression and immunosuppressive effects of TGF-β on NK cells. Taken together, we have identified fucosyltransferase 8 as a key modulator of NK cell development and function by regulating IL-15 receptor responsiveness.

2024-01-01 | GSE243190 | GEO

Impact of increased core fucosylation on the exosome proteome in prostate cancer

Project description:Prostate cancer is the most commonly diagnosed oncogenic malignancy in men worldwide, resulting in almost 30,000 cancer-related deaths in the United States each year. Wider examination of aberrant glycosylation in prostate cancer has revealed increased expression of the glycotransferase involved in core fucosylation, (1,6)fucosyltranferase (FUT8) associating with aggressive (AG) prostate cancer and castration-resistance, with functional analyses revealing FUT8 impacting cell motility and invasiveness in prostate cancer cells. Exosomes are extracellular microvesicles (30-150 nm) that are involved in in both proximal and distal intercellular communication via the transport of proteins and nucleic acids (mRNA, miRNA, and DNA). To gain insight into the impact of increased cellular FUT8 expression on exosome biogenesis and protein cargo profiles in prostate cancer, we paired Nanoparticle Tracking Analysis (NTA) and stable isotope labelling with amino acids in cell culture (SILAC) quantitative proteomics.

2020-05-13 | PXD013340 | Pride

Gene expression profiling of FUT8 knockdown CL1-5 cells

Project description:Overexpression of fucosyltransferase 8 (FUT8) is found in many cancers including liver, ovarian, thyroid, colorectal and non-small cell lung cancers. Unlike other FUTs which are functionally redundant, FUT8 is the only enzyme responsible for the alpha1,6-linked fucosylation (core fucosylation) by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions, such as EGFR, TGF beta receptor and integrins. To understand the downstream molecular events in response to the global alteration of core fucosylation during cancer progression, microarray analysis was employed to profile the changes in gene expression following FUT8 silencing. The genes significantly (2-fold, P<0.01) changed in CL1-5/shFUT8 cells were selected for functional annotations using a Gene Ontology database. The result revealed that many genes involved in cell adhesion, motility, growth, angiogenesis, and inflammation were under the control of core fucosylation.

2012-12-07 | GSE42405 | GEO

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