Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc

Jawad Abed; Johanna E.M. Emgård; Gideon Zamir; Mouhammad Faroja; Gideon Almogy; Amalie Grenov; Asaf Sol; Ronit Naor; Eli Pikarsky; Karine A. Atlan; Anna Mellul; Stella Chaushu; Abigail L. Manson; Ashlee M. Earl; Nora Ou; Caitlin A. Brennan; Wendy S. Garrett; Gilad Bachrach

doi:10.1016/j.chom.2016.07.006

Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc

Jawad Abed, Johanna E.M. Emgård, Gideon Zamir, Mouhammad Faroja, Gideon Almogy, Amalie Grenov, Asaf Sol, Ronit Naor, Eli Pikarsky, Karine A. Atlan, Anna Mellul, Stella Chaushu, Abigail L. Manson, Ashlee M. Earl, Nora Ou, Caitlin A. Brennan, Wendy S. Garrett^*, Gilad Bachrach

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

394 Scopus citations

Abstract

Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC.

Original language	American English
Pages (from-to)	215-225
Number of pages	11
Journal	Cell Host and Microbe
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.chom.2016.07.006
State	Published - 10 Aug 2016

Bibliographical note

Funding Information:
We thank Professor Lawrence A. Tabak for useful discussions, Professor Norman Grover for valuable assistance in statistics, and Carey Ann Gallini for proofreading. This work was supported by the Israel Cancer Research Fund Project grant and Israel Science Foundation grant 201/15 to G.B. and grant RO1 CA154426 and a Hoffman-LaRoche research grant to W.S.G. W.S.G. is a SAB member of Evelo Therapeutics and Synlogic, has received research funds from Hoffman-LaRoche, and consults for Janssen Pharmaceuticals.

Publisher Copyright:
© 2016 Elsevier Inc.

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Abed, J., Emgård, J. E. M., Zamir, G., Faroja, M., Almogy, G., Grenov, A., Sol, A., Naor, R., Pikarsky, E., Atlan, K. A., Mellul, A., Chaushu, S., Manson, A. L., Earl, A. M., Ou, N., Brennan, C. A., Garrett, W. S., & Bachrach, G. (2016). Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. Cell Host and Microbe, 20(2), 215-225. https://doi.org/10.1016/j.chom.2016.07.006

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title = "Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc",

abstract = "Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC.",

author = "Jawad Abed and Emg{\aa}rd, {Johanna E.M.} and Gideon Zamir and Mouhammad Faroja and Gideon Almogy and Amalie Grenov and Asaf Sol and Ronit Naor and Eli Pikarsky and Atlan, {Karine A.} and Anna Mellul and Stella Chaushu and Manson, {Abigail L.} and Earl, {Ashlee M.} and Nora Ou and Brennan, {Caitlin A.} and Garrett, {Wendy S.} and Gilad Bachrach",

note = "Funding Information: We thank Professor Lawrence A. Tabak for useful discussions, Professor Norman Grover for valuable assistance in statistics, and Carey Ann Gallini for proofreading. This work was supported by the Israel Cancer Research Fund Project grant and Israel Science Foundation grant 201/15 to G.B. and grant RO1 CA154426 and a Hoffman-LaRoche research grant to W.S.G. W.S.G. is a SAB member of Evelo Therapeutics and Synlogic, has received research funds from Hoffman-LaRoche, and consults for Janssen Pharmaceuticals. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = aug,

day = "10",

doi = "10.1016/j.chom.2016.07.006",

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Abed, J, Emgård, JEM, Zamir, G, Faroja, M, Almogy, G, Grenov, A, Sol, A, Naor, R, Pikarsky, E, Atlan, KA, Mellul, A, Chaushu, S, Manson, AL, Earl, AM, Ou, N, Brennan, CA, Garrett, WS & Bachrach, G 2016, 'Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc', Cell Host and Microbe, vol. 20, no. 2, pp. 215-225. https://doi.org/10.1016/j.chom.2016.07.006

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T1 - Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc

AU - Abed, Jawad

AU - Emgård, Johanna E.M.

AU - Zamir, Gideon

AU - Faroja, Mouhammad

AU - Almogy, Gideon

AU - Grenov, Amalie

AU - Sol, Asaf

AU - Naor, Ronit

AU - Pikarsky, Eli

AU - Atlan, Karine A.

AU - Mellul, Anna

AU - Chaushu, Stella

AU - Manson, Abigail L.

AU - Earl, Ashlee M.

AU - Ou, Nora

AU - Brennan, Caitlin A.

AU - Garrett, Wendy S.

AU - Bachrach, Gilad

N1 - Funding Information: We thank Professor Lawrence A. Tabak for useful discussions, Professor Norman Grover for valuable assistance in statistics, and Carey Ann Gallini for proofreading. This work was supported by the Israel Cancer Research Fund Project grant and Israel Science Foundation grant 201/15 to G.B. and grant RO1 CA154426 and a Hoffman-LaRoche research grant to W.S.G. W.S.G. is a SAB member of Evelo Therapeutics and Synlogic, has received research funds from Hoffman-LaRoche, and consults for Janssen Pharmaceuticals. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/8/10

Y1 - 2016/8/10

N2 - Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC.

AB - Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O-glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC.

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DO - 10.1016/j.chom.2016.07.006

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SN - 1931-3128

VL - 20

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JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 2

ER -

Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc

Abstract

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