An <i>In Vivo</i> Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor

Murugaesu, Nirupa; Iravani, Marjan; Weverwijk, Antoinette van; Ivetic, Aleksandar; Johnson, Damian A.; Antonopoulos, Aristotelis; Fearns, Antony; Jamal‐Hanjani, Mariam; Sims, David; Fenwick, Kerry; Mitsopoulos, Costas; Gao, Qiong; Orr, Nick; Zvelebil, Marketa; Haslam, Stuart M.; Dell, Anne; Yarwood, Helen; Lord, Christopher J.; Ashworth, Alan; Isacke, Clare M.

doi:10.1158/2159-8290.cd-13-0287

Cited by 81 publications

(86 citation statements)

References 49 publications

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“…Recent data suggest that high expression of α2,6 sialyltransferase ST6GalNAc2, which transfers sialic acid in a α2,6 linkage to N-acetylgalactosamine on Core 1 O-glycans (Marcos et al , 2004), prevents Gal-3-binding to unmodified Core 1 O-glycan (Murugaesu et al , 2014). Since Gal-1 binds extended Core 2 O-glycans, we investigated whether ST6GalNAc2 could neutralize O-glycan-dependent Gal-1 ligand activity.…”

Section: Resultsmentioning

confidence: 99%

“…Our data implicate melanoma Gal-1 ligands, notably N-glycosylated MCAM, and Gal-1-binding O-glycans negatively regulated by α2,6 sialyltransferase ST6GalNAc2 as pro-tumorigenic factors on melanoma cells. Prior data, in fact, show that MCAM expression directly correlates with melanoma metastasis (Kim et al , 2012; Luca et al , 1993; Mills et al , 2002; Xie et al , 1997) and ST6GalNAc2 also acts as a negative regulator of breast cancer metastasis by forming non-Gal-3-binding sialylated Core 1 O-glycans (Murugaesu et al , 2014). Our findings further highlight MCAM as a Gal-1 ligand and ST6GalNAc2 as a regulator of Gal-1 ligand activity in the glyco-pathogenesis of melanoma growth.…”

Section: Discussionmentioning

confidence: 99%

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Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential

Yazawa

Geddes-Sweeney

Cedeno-Laurent

et al. 2015

Journal of Investigative Dermatology

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Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening anti-tumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely-dysplastic nevi as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAMKD) or ST6GalNAc2-overexpressing (ST6O/E) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAMKD or ST6O/E melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1 – melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential

Yazawa

Geddes-Sweeney

Cedeno-Laurent

et al. 2015

Journal of Investigative Dermatology

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“…Recent reports now provide convincing evidence that O-glycan-modifying ST6GalNAcs regulate synthesis of Gal-1- and Gal-3-binding activity on cancer cells and related malignant activities conferred by interactions with host Gal-1 and Gal-3 (26, 47, 48). Heightened ST6GalNAc1-4 activities could result in a lower level of Gal-1-binding poly-N-acetyllactosamines on core 2 O-glycans or Gal-3-binding core 1 T antigens.…”

Section: B α26 Siaylation Of O-glycans and Its Impact On Cancer Promentioning

confidence: 99%

Galectin-Binding O-Glycosylations as Regulators of Malignancy

Dimitroff

2015

Cancer Research

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Cancer cells commonly display aberrant surface glycans and related glycoconjugate scaffolds. Compared with their normal counterparts, cancer cell glycans are variably produced and often structurally distinct, serving as biomarkers of cancer progression or as functional entities to malignancy. The glycan signature of a cancer cell is created by the collaborative activities of glycosyltransferases, glycosidases, nucleotide-sugar transporters, sulfotransferases and glycan-bearing protein/lipid scaffolds. In a coordinated fashion, these factors regulate the synthesis of cancer cell glycans and thus are considered correlates of cancer cell behavior. Functionally, cancer cell glycans can serve as binding targets for endogenous lectin effectors, such as C-type selectins and S-type galectins. There has been a recent surge of important observations on the role of glycosytransferases, specifically α2,6 sialyltransferases, in regulating the length and lectin-binding features of serine/threonine (O)-glycans found on cancer cells. The capping activity of O-glycan-specific α2,6 sialyltransferases, in particular, has been found to regulate cancer growth and metastasis in a galectin-dependent manner. These findings highlight the functional importance of cancer cell O-glycans and related galectin-binding features in the virulent activity of cancer and raise the prospect of targeting cancer cell glycans as effective anti-cancer therapeutics.

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“…S1A), and mice were treated with AC chemotherapy (2.5 mg/kg doxorubicin, 40 mg/kg of cyclophosphamide) or vehicle on days 2, 7, 11, and 16. On day 21, tumor burden was assessed by in vivo IVIS imaging and ex vivo lung weight, and gDNA was extracted from preinoculation cell pellets and tumor-bearing lungs (10). Supplementary Figure S1B outlines the strategy for combining samples prior to PCR amplification and highthroughput sequencing (15).…”

Section: Cells and Reagentsmentioning

confidence: 99%

“…However, such screens are unable to differentiate the mechanisms of greatest clinical relevance and may miss additional in vivo-specific drivers of response and resistance (6,7). In vivo RNAi screening has emerged as a physiologically relevant approach to explore gene function in tumor biology (8)(9)(10) and therapeutic response (11). In this study, we have adapted an in vivo short-hairpin (sh)RNAi approach combined with massively parallel sequencing to reveal novel determinants of response to anthracycline chemotherapy in a model of breast cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

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Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of firstline chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triplenegative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents.

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An In Vivo Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor

Cited by 81 publications

References 49 publications

Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential

Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential

Galectin-Binding O-Glycosylations as Regulators of Malignancy

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

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