A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis

Ferenc A. Scheeren; Angera H. Kuo; Linda J. Van Weele; Shang Cai; Iris Glykofridis; Shaheen S. Sikandar; Maider Zabala; Dalong Qian; Jessica S. Lam; Darius Johnston; Jens P. Volkmer; Debashis Sahoo; Matt Van De Rijn; Frederick M. Dirbas; George Somlo; Tomer Kalisky; Michael E. Rothenberg; Stephen R. Quake; Michael F. Clarke

doi:10.1038/ncb3058

A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis

Ferenc A. Scheeren, Angera H. Kuo, Linda J. Van Weele, Shang Cai, Iris Glykofridis, Shaheen S. Sikandar, Maider Zabala, Dalong Qian, Jessica S. Lam, Darius Johnston, Jens P. Volkmer, Debashis Sahoo, Matt Van De Rijn, Frederick M. Dirbas, George Somlo, Tomer Kalisky, Michael E. Rothenberg, Stephen R. Quake, Michael F. Clarke

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

109 Scopus citations

Abstract

It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

Original language	English
Pages (from-to)	1238-1248
Number of pages	11
Journal	Nature Cell Biology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/ncb3058
State	Published - 1 Dec 2014

Bibliographical note

Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.

Funding

This study was supported by the National Institutes of Health (NCI), the Breast Cancer Research Foundation, the Ludwig Institute, The California Institute for Regenerative Medicine and the Department of Defense (DOD). F.A.S. was supported by NWO-Rubicon grant, a fellowship from the Dutch Cancer Society and by a seed grant of the organization My Blue Dots. We thank T.N. Schumacher and M.A. Child for scientific input, S. Sim for her assistance with single-cell PCR assays, P. Lovelace for her assistance with flow cytometry and K. Montgomery for IHC. Some research was performed on a FACS Aria that was purchased using NIH S10 Shared Instrumentation Grant (1S10RR02933801) funds.

Funders	Funder number
Dutch Cancer Society
Ludwig Institute
NWO-Rubicon
National Institutes of Health
U.S. Department of Defense
National Cancer Institute
California Institute for Regenerative Medicine
Breast Cancer Research Foundation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Scheeren, F. A., Kuo, A. H., Van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., Van De Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., & Clarke, M. F. (2014). A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nature Cell Biology, 16(12), 1238-1248. https://doi.org/10.1038/ncb3058

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abstract = "It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.",

author = "Scheeren, {Ferenc A.} and Kuo, {Angera H.} and {Van Weele}, {Linda J.} and Shang Cai and Iris Glykofridis and Sikandar, {Shaheen S.} and Maider Zabala and Dalong Qian and Lam, {Jessica S.} and Darius Johnston and Volkmer, {Jens P.} and Debashis Sahoo and {Van De Rijn}, Matt and Dirbas, {Frederick M.} and George Somlo and Tomer Kalisky and Rothenberg, {Michael E.} and Quake, {Stephen R.} and Clarke, {Michael F.}",

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Scheeren, FA, Kuo, AH, Van Weele, LJ, Cai, S, Glykofridis, I, Sikandar, SS, Zabala, M, Qian, D, Lam, JS, Johnston, D, Volkmer, JP, Sahoo, D, Van De Rijn, M, Dirbas, FM, Somlo, G, Kalisky, T, Rothenberg, ME, Quake, SR & Clarke, MF 2014, 'A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis', Nature Cell Biology, vol. 16, no. 12, pp. 1238-1248. https://doi.org/10.1038/ncb3058

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AU - Scheeren, Ferenc A.

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AU - Cai, Shang

AU - Glykofridis, Iris

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AU - Lam, Jessica S.

AU - Johnston, Darius

AU - Volkmer, Jens P.

AU - Sahoo, Debashis

AU - Van De Rijn, Matt

AU - Dirbas, Frederick M.

AU - Somlo, George

AU - Kalisky, Tomer

AU - Rothenberg, Michael E.

AU - Quake, Stephen R.

AU - Clarke, Michael F.

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A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis

Abstract

Bibliographical note

Funding

UN SDGs

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