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SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth

Anjali Balakrishnan, Lata Adnani, Vorapin Chinchalongporn, Lakshmy Vasan, Oleksandr Prokopchuk, Myra J Chen, Ahmed El-Sehemy, Thomas Olender, Yacine Touahri, Shiekh Tanveer Ahmad, Rehnuma Islam, Sajeevan Sujanthan, Dawn Zinyk, Lacrimioara C Comanita, Boris Kan, Taylor Fleming, Hon S Leong, Cindi M Morshead, Marjorie Brand, Valerie A Wallace, Jennifer A Chan, Carol Schuurmans
doi: https://doi.org/10.1101/2020.07.14.202200
Anjali Balakrishnan
1Sunnybrook Research Institute, Toronto, ON, Canada
2Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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Lata Adnani
1Sunnybrook Research Institute, Toronto, ON, Canada
3Department of Biochemistry and Molecular Biology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
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Vorapin Chinchalongporn
1Sunnybrook Research Institute, Toronto, ON, Canada
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Lakshmy Vasan
1Sunnybrook Research Institute, Toronto, ON, Canada
4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Oleksandr Prokopchuk
1Sunnybrook Research Institute, Toronto, ON, Canada
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Myra J Chen
5Department of Pathology and Laboratory Medicine, Charbonneau Cancer Institute, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
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Ahmed El-Sehemy
4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
6Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network
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Thomas Olender
7Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Yacine Touahri
1Sunnybrook Research Institute, Toronto, ON, Canada
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Shiekh Tanveer Ahmad
5Department of Pathology and Laboratory Medicine, Charbonneau Cancer Institute, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
8Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, USA
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Rehnuma Islam
9Department of Surgery, University of Toronto, Toronto, ON, Canada
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Sajeevan Sujanthan
1Sunnybrook Research Institute, Toronto, ON, Canada
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Dawn Zinyk
1Sunnybrook Research Institute, Toronto, ON, Canada
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Lacrimioara C Comanita
6Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network
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Boris Kan
1Sunnybrook Research Institute, Toronto, ON, Canada
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Taylor Fleming
1Sunnybrook Research Institute, Toronto, ON, Canada
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Hon S Leong
1Sunnybrook Research Institute, Toronto, ON, Canada
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Cindi M Morshead
9Department of Surgery, University of Toronto, Toronto, ON, Canada
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Marjorie Brand
7Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Valerie A Wallace
4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
6Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network
10Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
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Jennifer A Chan
3Department of Biochemistry and Molecular Biology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
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Carol Schuurmans
1Sunnybrook Research Institute, Toronto, ON, Canada
2Department of Biochemistry, University of Toronto, Toronto, ON, Canada
3Department of Biochemistry and Molecular Biology, Alberta Children’s Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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  • For correspondence: cschuurm@sri.utoronto.ca
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ABSTRACT

Oligodendrogliomas are lower-grade, slow-growing gliomas that are ultimately fatal. Although driver mutations are known, the mechanisms underlying their signature slow growth rates are poorly understood. We found evidence for intra-tumoral interactions between neoplastic and non-neoplastic cells in oligodendroglioma tissues. To further study these cell interactions, we used two patient-derived oligodendroglioma cell lines of lower and higher aggressivity. Both oligodendroglioma cell lines released extracellular vesicles that had cytotoxic effects on non-neoplastic and neoplastic cells, but each had distinct vesicular proteomes. Consistent with extracellular vesicles mediating growth inhibitory effects in oligodendrogliomas, higher expression levels of several extracellular vesicle biogenesis genes (SMPD3,TSG101, STAM1) correlates with longer survival in oligodendroglioma patients. Furthermore, SMPD3 overexpression slows oligodendroglioma cell growth in culture. Conversely, SMPD3 knockdown enhances oligodendroglioma proliferation in vitro, in murine xenografts, and in human cerebral organoid co-cultures. Oligodendroglioma-derived extracellular vesicles thus mediate tumor cell microenvironmental interactions that contribute to low aggressivity.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* co-senior authors

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SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth
Anjali Balakrishnan, Lata Adnani, Vorapin Chinchalongporn, Lakshmy Vasan, Oleksandr Prokopchuk, Myra J Chen, Ahmed El-Sehemy, Thomas Olender, Yacine Touahri, Shiekh Tanveer Ahmad, Rehnuma Islam, Sajeevan Sujanthan, Dawn Zinyk, Lacrimioara C Comanita, Boris Kan, Taylor Fleming, Hon S Leong, Cindi M Morshead, Marjorie Brand, Valerie A Wallace, Jennifer A Chan, Carol Schuurmans
bioRxiv 2020.07.14.202200; doi: https://doi.org/10.1101/2020.07.14.202200
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SMPD3-mediated extracellular vesicle biogenesis inhibits oligodendroglioma growth
Anjali Balakrishnan, Lata Adnani, Vorapin Chinchalongporn, Lakshmy Vasan, Oleksandr Prokopchuk, Myra J Chen, Ahmed El-Sehemy, Thomas Olender, Yacine Touahri, Shiekh Tanveer Ahmad, Rehnuma Islam, Sajeevan Sujanthan, Dawn Zinyk, Lacrimioara C Comanita, Boris Kan, Taylor Fleming, Hon S Leong, Cindi M Morshead, Marjorie Brand, Valerie A Wallace, Jennifer A Chan, Carol Schuurmans
bioRxiv 2020.07.14.202200; doi: https://doi.org/10.1101/2020.07.14.202200

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