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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 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

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Pavel Sinitcyn

LAB HEAD: Prof. Yoosik Kim

PROVIDER: PXD022240 | Pride | 2023-04-05

REPOSITORIES: Pride

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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 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.

2023-04-05 | GSE160205 | GEO

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

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

Gene expression profiling of FUT8 knockdown CL1-5 cells

2012-12-07 | E-GEOD-42405 | biostudies-arrayexpress

Decreased IgG core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases

Project description:Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins (Igs) and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells (PBMCs) glycosylation with AITD and the influence of genetic background. The study revealed an inverse association of IgG core fucosylation with TPOAb and PBMCs antennary α1,2 fucosylation with AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity (ADCC) associated with TPOAb levels

2020-02-14 | PXD015684 | Pride

Characterization and therapeutic repercussion of the ecology in HER2 positive breast cancer

Project description:Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of CAF-conditioned medium that would be relevant in the promotion of BCCL resistance, we performed a multi-omics strategy to identify miRNAs, cytokines, transcription factors and/or kinases in the secretome that target specific objectives in cancer cells. The combination of miRNA analysis, label-free LC-MS/MS quantification and cytokine arrays to explore the secretome of CAFs under treatment conditions revealed several up- and down-regulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer

2022-01-26 | PXD025556 | Pride

Identification of Distinct N-Glycosylation Patterns on Extracellular Vesicles from Small-Cell and Non-Small-Cell Lung Cancer Cells

Project description:Asparagine-linked glycosylation (N-glycosylation) of proteins in the cancer secretome has gained increasing attention as a potential biomarker for cancer detection and diagnosis. Small extracellular vesicles (sEVs) constitute a large part of the cancer secretome, yet little is known about whether their N-glycosylation status reflects cancer characteristics. Here we investigated the N-glycosylation of sEVs released from small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC) cells. The N-glycans of SCLC-sEVs were characterized by the presence of structural units found in the brain N-glycome, while NSCLC-sEVs were dominated by typical lung-type N-glycans with NSCLC-associated core fucosylation. We pulled down these glycoproteins from the detergent-solubilized sEVs with SSA-conjugated beads for H520-sEVs and WGA-conjugated beads for H446-sEVs, and the protein bands were subjected to shotgun proteomics. The analysis revealed that several integrin subunits were enriched in the sEVs: V, 6, 1, and 5 subunits in H520-sEVs and V and 1 subunits in H446-sEVs.

2022-06-09 | PXD030865 | Pride

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

Repeated gestational exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1)-modulated effects in maternal and fetal tissues

Project description:Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured biomarker inhibition and fetal-brain gene expression in wild-type (PON1+/+), PON1-knockout (PON1-/-), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75 or 0.85 mg/kg/d CPO from gestational days (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), RBC acylpeptide hydrolase (APH), plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1-/- and tgHuPON1Q192, but not PON1+/+ or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1-/- mice, but not in other genotypes.

2014-08-04 | GSE58103 | GEO

Cerebellum from mice exposed to chronic low-level chlorpyrifos oxon

Project description:Chlorpyrifos (CPF) is an organophosphorus (OP) insecticide that is still widely used despite statutory restrictions on home use. CPF is converted to chlorpyrifos oxon (CPO) by oxidative desulfuration in liver. Paraoxonase (PON1) polymorphisms affects the catalytic efficiency of the hydrolysis of OPs, including CPO. We used both wt (PON1+/+) and PON1 knockout (PON1-/-) mice and PON1-/- mice carrying transgenes encoding the human alloforms tgHuPON1Q192 and tgHuPON1R192 to gain insight into the mechanisms of neurotoxicity of CPO throughout postnatal development, and to ascertain the importance of the PON1Q192R polymorphism for protecting against developmental toxicity of CPO. Whole-genome microarrays were used to measure gene expression changes associated with chronic CPO exposure of developing (PND 4-21) PON1-/-, tgHuPON1Q192R transgenic and PON1+/+ mice. Expression profiles are derived from cerebella from wild-type C57/Bl6 and PON1-/- on a C57/Bl6 background and two transgenic strains (tgHuPON1Q192, tgHuPON1R192) expressing either human PON1Q192 or human PON1R192 on the PON1-/- C57/Bl6 background. The mice were subjected to chronic postnatal exposure to CPO (CPO).

2011-11-09 | GSE25250 | GEO

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