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Revealing the human mucinome

View ORCID ProfileStacy A. Malaker, View ORCID ProfileNicholas M. Riley, View ORCID ProfileD. Judy Shon, View ORCID ProfileKayvon Pedram, Venkatesh Krishnan, View ORCID ProfileOliver Dorigo, View ORCID ProfileCarolyn R. Bertozzi
doi: https://doi.org/10.1101/2021.01.27.428510
Stacy A. Malaker
1Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305
2Department of Chemistry, Yale University, New Haven CT, 06511
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  • For correspondence: stacy.malaker@yale.edu bertozzi@stanford.edu
Nicholas M. Riley
1Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305
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D. Judy Shon
1Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305
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Kayvon Pedram
1Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305
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Venkatesh Krishnan
3Stanford Women’s Cancer Center, Division of Gynecologic Oncology, Stanford University, Stanford, CA 94305
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Oliver Dorigo
3Stanford Women’s Cancer Center, Division of Gynecologic Oncology, Stanford University, Stanford, CA 94305
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Carolyn R. Bertozzi
1Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA 94305
4Howard Hughes Medical Institute, Stanford, CA 94305
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  • For correspondence: stacy.malaker@yale.edu bertozzi@stanford.edu
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Abstract

Mucin domains are densely O-glycosylated modular protein domains found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are key players in a host of human diseases, especially cancer, but the scope of the mucinome remains poorly defined. Recently, we characterized a bacterial mucinase, StcE, and demonstrated that an inactive point mutant retains binding selectivity for mucins. In this work, we leveraged inactive StcE to selectively enrich and identify mucins from complex samples like cell lysate and crude ovarian cancer patient ascites fluid. Our enrichment strategy was further aided by an algorithm to assign confidence to mucin-domain glycoprotein identifications. This mucinomics platform facilitated detection of hundreds of glycopeptides from mucin domains and highly overlapping populations of mucin-domain glycoproteins from ovarian cancer patients. Ultimately, we demonstrate our mucinomics approach can reveal key molecular signatures of cancer from in vitro and ex vivo sources.

Competing Interest Statement

S.A.M., D.J.S., K.P., and C.R.B. are coinventors on a Stanford patent application related to this work. C.R.B. is a co-founder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company. O.D. has participated in advisory boards for Tesaro, Merck, and Geneos. O.D. is a speaker for Tesaro and AstraZeneca.

Footnotes

  • Conflict of Interest Statement S.A.M., D.J.S., K.P., and C.R.B. are coinventors on a Stanford patent application related to this work. C.R.B. is a co-founder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company. O.D. has participated in advisory boards for Tesaro, Merck, and Geneos. O.D. is a speaker for Tesaro and AstraZeneca.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 28, 2021.
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Revealing the human mucinome
Stacy A. Malaker, Nicholas M. Riley, D. Judy Shon, Kayvon Pedram, Venkatesh Krishnan, Oliver Dorigo, Carolyn R. Bertozzi
bioRxiv 2021.01.27.428510; doi: https://doi.org/10.1101/2021.01.27.428510
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Revealing the human mucinome
Stacy A. Malaker, Nicholas M. Riley, D. Judy Shon, Kayvon Pedram, Venkatesh Krishnan, Oliver Dorigo, Carolyn R. Bertozzi
bioRxiv 2021.01.27.428510; doi: https://doi.org/10.1101/2021.01.27.428510

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