Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils

Camilla Engblom; Christina Pfirschke; Rapolas Zilionis; Janaina Da Silva Martins; Stijn A. Bos; Gabriel Courties; Steffen Rickelt; Nicolas Severe; Ninib Baryawno; Julien Faget; Virginia Savova; David Zemmour; Jaclyn Kline; Marie Siwicki; Christopher Garris; Ferdinando Pucci; Hsin Wei Liao; Yi Jang Lin; Andita Newton; Omar K. Yaghi; Yoshiko Iwamoto; Benoit Tricot; Gregory R. Wojtkiewicz; Matthias Nahrendorf; Virna Cortez-Retamozo; Etienne Meylan; Richard O. Hynes; Marie Demay; Allon Klein; Miriam A. Bredella; David T. Scadden; Ralph Weissleder; Mikael J. Pittet

doi:10.1126/science.aal5081

Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils

Camilla Engblom, Christina Pfirschke, Rapolas Zilionis, Janaina Da Silva Martins, Stijn A. Bos, Gabriel Courties, Steffen Rickelt, Nicolas Severe, Ninib Baryawno, Julien Faget, Virginia Savova, David Zemmour, Jaclyn Kline, Marie Siwicki, Christopher Garris, Ferdinando Pucci, Hsin Wei Liao, Yi Jang Lin, Andita Newton, Omar K. YaghiYoshiko Iwamoto, Benoit Tricot, Gregory R. Wojtkiewicz, Matthias Nahrendorf, Virna Cortez-Retamozo, Etienne Meylan, Richard O. Hynes, Marie Demay, Allon Klein, Miriam A. Bredella, David T. Scadden, Ralph Weissleder, Mikael J. Pittet

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Abstract

Bone marrow–derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn⁺) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF^high neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn⁺ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF^high neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.

Original language	English (US)
Article number	eaal5081
Journal	Science
Volume	358
Issue number	6367
DOIs	https://doi.org/10.1126/science.aal5081
State	Published - Dec 1 2017
Externally published	Yes

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Engblom, C., Pfirschke, C., Zilionis, R., Da Silva Martins, J., Bos, S. A., Courties, G., Rickelt, S., Severe, N., Baryawno, N., Faget, J., Savova, V., Zemmour, D., Kline, J., Siwicki, M., Garris, C., Pucci, F., Liao, H. W., Lin, Y. J., Newton, A., ... Pittet, M. J. (2017). Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils. Science, 358(6367), [eaal5081]. https://doi.org/10.1126/science.aal5081

Engblom, C, Pfirschke, C, Zilionis, R, Da Silva Martins, J, Bos, SA, Courties, G, Rickelt, S, Severe, N, Baryawno, N, Faget, J, Savova, V, Zemmour, D, Kline, J, Siwicki, M, Garris, C, Pucci, F, Liao, HW, Lin, YJ, Newton, A, Yaghi, OK, Iwamoto, Y, Tricot, B, Wojtkiewicz, GR, Nahrendorf, M, Cortez-Retamozo, V, Meylan, E, Hynes, RO, Demay, M, Klein, A, Bredella, MA, Scadden, DT, Weissleder, R & Pittet, MJ 2017, 'Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils', Science, vol. 358, no. 6367, eaal5081. https://doi.org/10.1126/science.aal5081

@article{1409ced00ce449a08ba8b9a19561dee5,

title = "Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils",

abstract = "Bone marrow–derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.",

author = "Camilla Engblom and Christina Pfirschke and Rapolas Zilionis and {Da Silva Martins}, Janaina and Bos, {Stijn A.} and Gabriel Courties and Steffen Rickelt and Nicolas Severe and Ninib Baryawno and Julien Faget and Virginia Savova and David Zemmour and Jaclyn Kline and Marie Siwicki and Christopher Garris and Ferdinando Pucci and Liao, {Hsin Wei} and Lin, {Yi Jang} and Andita Newton and Yaghi, {Omar K.} and Yoshiko Iwamoto and Benoit Tricot and Wojtkiewicz, {Gregory R.} and Matthias Nahrendorf and Virna Cortez-Retamozo and Etienne Meylan and Hynes, {Richard O.} and Marie Demay and Allon Klein and Bredella, {Miriam A.} and Scadden, {David T.} and Ralph Weissleder and Pittet, {Mikael J.}",

note = "Funding Information: We thank the Harvard Stem Cell Institute for help with FACS sorting; D. Brooks, M. Scott, and M. Bouxsein from the Center for Skeletal Research Core (NIH grant P30-AR066261) for mCT bone analysis services; members of the Hope Babette Tang Histology Facility at the Koch Institute Swanson Biotechnology Center for technical support; M. Wein for helpful discussions and technical assistance; and D. Mathis, C. Benoist, S. Pillai, S. McAllister, and G. Dranoff for their input. This work was supported in part by the Samana Cay MGH (Massachusetts General Hospital) Research Scholar Fund, the Robert Wenner Award from the Swiss Cancer League, and NIH grants R01-AI084880, R01-CA206890, and P50-CA86355 (to M.J.P.); NIH grant U54-CA126515 (to R.W.); NIH grant CA148180 (to D.T.S.); NIH grant U54-CA163109 and the Howard Hughes Medical Institute (to R.O.H.); NIH grant R33-CA212697 and an Edward J. Mallinckrodt Jr. Fellowship (to A.K.); Boehringer Ingelheim Fonds PhD fellowships (to C.E. and D.Z.); Deutsche Forschungsgemeinschaft PF809/1-1 and MGH ECOR (Executive Committee on Research) Tosteson Postdoctoral Fellowship (to C.P.); a postdoctoral fellowship from the MIT (Massachusetts Institute of Technology) Ludwig Center for Molecular Oncology Research (to S.R.); and award T32-GM007753 from the National Institute of General Medical Sciences (to O.K.Y.). A.K. is a founder of, and is on the Scientific Advisory Board of, 1CellBio. R.O.H. is a scientific advisor for Genentech and Amgen. M.J.P., C.E., and C.P. are inventors on patent application 62/ 489,118 filed by MGH that covers the detection and targeting of tumor-promoting neutrophils. Osteoblast RNA-seq data have been deposited to the GEO (Gene Expression Omnibus) repository under the accession number GSE104294. Publisher Copyright: {\textcopyright} 2017, American Association for the Advancement of Science. All rights reserved.",

year = "2017",

month = dec,

day = "1",

doi = "10.1126/science.aal5081",

language = "English (US)",

volume = "358",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6367",

}

TY - JOUR

T1 - Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils

AU - Engblom, Camilla

AU - Pfirschke, Christina

AU - Zilionis, Rapolas

AU - Da Silva Martins, Janaina

AU - Bos, Stijn A.

AU - Courties, Gabriel

AU - Rickelt, Steffen

AU - Severe, Nicolas

AU - Baryawno, Ninib

AU - Faget, Julien

AU - Savova, Virginia

AU - Zemmour, David

AU - Kline, Jaclyn

AU - Siwicki, Marie

AU - Garris, Christopher

AU - Pucci, Ferdinando

AU - Liao, Hsin Wei

AU - Lin, Yi Jang

AU - Newton, Andita

AU - Yaghi, Omar K.

AU - Iwamoto, Yoshiko

AU - Tricot, Benoit

AU - Wojtkiewicz, Gregory R.

AU - Nahrendorf, Matthias

AU - Cortez-Retamozo, Virna

AU - Meylan, Etienne

AU - Hynes, Richard O.

AU - Demay, Marie

AU - Klein, Allon

AU - Bredella, Miriam A.

AU - Scadden, David T.

AU - Weissleder, Ralph

AU - Pittet, Mikael J.

N1 - Funding Information: We thank the Harvard Stem Cell Institute for help with FACS sorting; D. Brooks, M. Scott, and M. Bouxsein from the Center for Skeletal Research Core (NIH grant P30-AR066261) for mCT bone analysis services; members of the Hope Babette Tang Histology Facility at the Koch Institute Swanson Biotechnology Center for technical support; M. Wein for helpful discussions and technical assistance; and D. Mathis, C. Benoist, S. Pillai, S. McAllister, and G. Dranoff for their input. This work was supported in part by the Samana Cay MGH (Massachusetts General Hospital) Research Scholar Fund, the Robert Wenner Award from the Swiss Cancer League, and NIH grants R01-AI084880, R01-CA206890, and P50-CA86355 (to M.J.P.); NIH grant U54-CA126515 (to R.W.); NIH grant CA148180 (to D.T.S.); NIH grant U54-CA163109 and the Howard Hughes Medical Institute (to R.O.H.); NIH grant R33-CA212697 and an Edward J. Mallinckrodt Jr. Fellowship (to A.K.); Boehringer Ingelheim Fonds PhD fellowships (to C.E. and D.Z.); Deutsche Forschungsgemeinschaft PF809/1-1 and MGH ECOR (Executive Committee on Research) Tosteson Postdoctoral Fellowship (to C.P.); a postdoctoral fellowship from the MIT (Massachusetts Institute of Technology) Ludwig Center for Molecular Oncology Research (to S.R.); and award T32-GM007753 from the National Institute of General Medical Sciences (to O.K.Y.). A.K. is a founder of, and is on the Scientific Advisory Board of, 1CellBio. R.O.H. is a scientific advisor for Genentech and Amgen. M.J.P., C.E., and C.P. are inventors on patent application 62/ 489,118 filed by MGH that covers the detection and targeting of tumor-promoting neutrophils. Osteoblast RNA-seq data have been deposited to the GEO (Gene Expression Omnibus) repository under the accession number GSE104294. Publisher Copyright: © 2017, American Association for the Advancement of Science. All rights reserved.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Bone marrow–derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.

AB - Bone marrow–derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.

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DO - 10.1126/science.aal5081

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VL - 358

JO - Science

JF - Science

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M1 - eaal5081

ER -

Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF^high neutrophils

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