Terminal α2,6-sialylation of epidermal growth factor receptor modulates antibody therapy response of colorectal cancer cells

Rodrigues, Joana G.; Duarte, Hugo; Gomes, Catarina; Balmaña, Meritxell; Martins, Álvaro M; Hensbergen, Paul J.; Ru, Arnoud H. de; Lima, Jorge; Albergaria, André; Veelen, Peter A. van; Wuhrer, Manfred; Gomes, Joana; Reis, Celso A.

doi:10.1007/s13402-021-00606-z

Cited by 29 publications

(27 citation statements)

References 53 publications

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“…Our studies support this concept, and furthermore indicate that ST6Gal1 in BCP-ALL is neither an oncogene nor a tumor suppressor. This does not exclude an important contribution of ST6Gal1 to the outcome of specific therapies such as those making use of monoclonal antibodies, as described for the EGFR and ErbB2 (59,60). However, detailed analytical glycan studies of sialylation on CD19, CD22, or CD20 glycoproteins before and after treatment with antibodies or CAR Tcells would be needed to determine if ST6Gal1 N-linked a2,6 sialylation is a contributing factor to resistance in B-cell malignancies treated with such immune therapies.…”

Section: Discussionmentioning

confidence: 99%

“…In some carcinomas, glycoproteins such as the EGFR and ErbB2 function as critical oncogenes that consistently drive the tumor phenotype. Interestingly, ST6Gal1 sialylation of these receptors was linked to sensitivity to cetuximab and trastuzumab therapeutic monoclonal antibodies ( 59 , 60 ). Unfortunately, whether BCP-ALL cells of all subtypes and at different stages of treatment (diagnosis and relapse) consistently express one or more of such glycoproteins, of which the α2,6 N-linked sialylation would be critical for cell growth or drug resistance, remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

Zhang

Yang

et al. 2022

Front. Oncol.

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Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of ST6GAL1 at diagnosis, with high ST6Gal1 in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

Zhang

Yang

et al. 2022

Front. Oncol.

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“…In the past, we and other groups have demonstrated how glycosylation may increase the cancer specificity of proteins, which could be explored for precise cancer-targeting 25 , 31 , 32 , 34 , 47 , 48 . CD44 presents multiple potential O -glycosylation sites in its extracellular domain, mostly in the variable region, which could be explored towards this objective 2 .…”

Section: Methodsmentioning

confidence: 99%

Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion

Gaiteiro¹,

Soares²,

Relvas-Santos³

et al. 2022

Theranostics

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Rationale: Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine. Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells. However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles. The lack of tools for precise molecular characterization has led to conflicting results, delaying clinical applications. Addressing these limitations, we have interrogated the transcriptome and glycoproteome of a large BC patient cohort for splicing signatures. Methods: CD44 gene and its splicing variants were assessed by Real Time-Polymerase Chain Reaction (RT-PCR) and RNAseq in tumor tissues. The co-localization of CD44 and short O -glycans was evaluated by proximity ligation assay (PLA), immunohistochemistry and double-immunofluorescence. An innovative glycoproteogenomics approach, integrating transcriptomics-customized datasets and glycomics for protein annotation from nanoLC-ESI-MS/MS experiments, was developed and implemented to identify CD44 variants and associated glycosignatures. The impact of CD44 silencing on proliferation and invasion of BC cell lines and glycoengineered cells was determined by BrdU ELISA and Matrigel invasion assays, respectively. Antibody phosphoarrays were used to investigate the role of CD44 and its glycoforms in the activation of relevant oncogenic signaling pathways. Results: Transcriptomics analysis revealed remarkable CD44 isoforms heterogeneity in bladder cancer tissues, as well as associations between short CD44 standard splicing isoform (CD44s), invasion and poor prognosis. We further demonstrated that targeting short O -glycoforms such as the Tn and sialyl-Tn antigens was key to overcome the lack of cancer specificity presented by CD44. Glycoproteogenomics allowed, for the first time, the comprehensive characterization of CD44 splicing code at the protein level. The concept was applied to invasive human BC cell lines, glycoengineered cells, and tumor tissues, enabling unequivocal CD44s identification as well as associated glycoforms. Finally, we confirmed the link between CD44 and invasion in CD44s-enriched cells in vitro by small interfering RNA (siRNA) knockdown, supporting findings from BC tissues. The key role played by short-chain O -glycans in CD44-mediated invasion was also demonstrated through glycoengineered cell models. Conclusions: Overall, CD44s emerged as biomarker of poor prognosis and CD44-Tn/ Sialyl-Tn (STn) as promising molecular signatures for targeted interventions. This study materializes the concept of glycoproteogenomics and provides a key vision to address the cancer splicing code at the protein level, which may now be expanded to better understand CD44 functional role in ...

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“…Receptor tyrosine kinases (RTKs) and their downstream signaling cascades actively drive neoplastic transformation. Moreover, several studies have demonstrated that the altered glycosylation of different RTKs (such as EGFR, ErbB2, Met, and RON) leads to their hyperactivation, which, in turn, promotes RTK-dependent malignant growth and phenotypically aggressive tumors [ 16 , 17 , 18 , 19 , 20 ].…”

Section: Glycosylation In Cancermentioning

confidence: 99%

Glycans as Targets for Drug Delivery in Cancer

Diniz

Coelho

Duarte

et al. 2022

Cancers

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Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody–drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors.

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Terminal α2,6-sialylation of epidermal growth factor receptor modulates antibody therapy response of colorectal cancer cells

Cited by 29 publications

References 53 publications

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia

Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion

Glycans as Targets for Drug Delivery in Cancer

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