Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility

Thomas Mandel Clausen; Marina Maria Bento Ayres Pereira; Nader Al Nakouzi; Htoo Zarni Oo; Mette Ø Agerbæk; Sherry Lee; Maj Sofie Ørum-Madsen; Anders Riis Kristensen; Amal El-Naggar; Paul M Grandgenett; Jean L Grem; Michael A Hollingsworth; Peter J Holst; Thor Theander; Poul H Sorensen; Mads Daugaard; Ali Salanti

doi:10.1158/1541-7786.mcr-16-0103

Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility

Thomas Mandel Clausen, Marina Maria Bento Ayres Pereira, Nader Al Nakouzi, Htoo Zarni Oo, Mette Ø Agerbæk, Sherry Lee, Maj Sofie Ørum-Madsen, Anders Riis Kristensen, Amal El-Naggar, Paul M Grandgenett, Jean L Grem, Michael A Hollingsworth, Peter J Holst, Thor Theander, Poul H Sorensen, Mads Daugaard, Ali Salanti

29 Citations (Scopus)

Abstract

Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.

Original language	English
Journal	Molecular Cancer Research
Volume	14
Issue number	12
Pages (from-to)	1288-1299
Number of pages	12
ISSN	1541-7786
DOIs	https://doi.org/10.1158/1541-7786.mcr-16-0103
Publication status	Published - 1 Dec 2016

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Clausen, T. M., Bento Ayres Pereira, M. M., Al Nakouzi, N., Oo, H. Z., Agerbæk, M. Ø., Lee, S., Ørum-Madsen, M. S., Kristensen, A. R., El-Naggar, A., Grandgenett, P. M., Grem, J. L., Hollingsworth, M. A., Holst, P. J., Theander, T., Sorensen, P. H., Daugaard, M., & Salanti, A. (2016). Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility. Molecular Cancer Research, 14(12), 1288-1299. https://doi.org/10.1158/1541-7786.mcr-16-0103

Clausen, TM , Bento Ayres Pereira, MM, Al Nakouzi, N, Oo, HZ, Agerbæk, MØ, Lee, S, Ørum-Madsen, MS, Kristensen, AR, El-Naggar, A, Grandgenett, PM, Grem, JL, Hollingsworth, MA, Holst, PJ , Theander, T, Sorensen, PH, Daugaard, M & Salanti, A 2016, 'Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility', Molecular Cancer Research, vol. 14, no. 12, pp. 1288-1299. https://doi.org/10.1158/1541-7786.mcr-16-0103

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title = "Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility",

abstract = "Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.",

author = "Clausen, {Thomas Mandel} and {Bento Ayres Pereira}, {Marina Maria} and {Al Nakouzi}, Nader and Oo, {Htoo Zarni} and Agerb{\ae}k, {Mette {\O}} and Sherry Lee and {\O}rum-Madsen, {Maj Sofie} and Kristensen, {Anders Riis} and Amal El-Naggar and Grandgenett, {Paul M} and Grem, {Jean L} and Hollingsworth, {Michael A} and Holst, {Peter J} and Thor Theander and Sorensen, {Poul H} and Mads Daugaard and Ali Salanti",

note = "{\textcopyright}2016 American Association for Cancer Research.",

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doi = "10.1158/1541-7786.mcr-16-0103",

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pages = "1288--1299",

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T1 - Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility

AU - Clausen, Thomas Mandel

AU - Bento Ayres Pereira, Marina Maria

AU - Al Nakouzi, Nader

AU - Oo, Htoo Zarni

AU - Agerbæk, Mette Ø

AU - Lee, Sherry

AU - Ørum-Madsen, Maj Sofie

AU - Kristensen, Anders Riis

AU - El-Naggar, Amal

AU - Grandgenett, Paul M

AU - Grem, Jean L

AU - Hollingsworth, Michael A

AU - Holst, Peter J

AU - Theander, Thor

AU - Sorensen, Poul H

AU - Daugaard, Mads

AU - Salanti, Ali

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.

AB - Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion, and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin-β1 (ITGB1) and integrin-α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core chondroitin sulfate synthesis enzymes β-1,3-glucuronyltransferase 1 (B3GAT1) and chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGAL-NACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and preincubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications: The cancer-specific expression of ofCS aids in metastatic phenotypes and is a candidate target for therapy.

U2 - 10.1158/1541-7786.mcr-16-0103

DO - 10.1158/1541-7786.mcr-16-0103

M3 - Journal article

C2 - 27655130

SN - 1541-7786

VL - 14

SP - 1288

EP - 1299

JO - Molecular Cancer Research

JF - Molecular Cancer Research

IS - 12

ER -

Oncofetal chondroitin sulfate glycosaminoglycans are key players in integrin signaling and tumor cell motility

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