Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis

Gonçalo Rodrigues; Ayuko Hoshino; Candia M. Kenific; Irina R. Matei; Loïc Steiner; Daniela Freitas; Han Sang Kim; Peter R. Oxley; Ilana Scandariato; Irene Casanova-Salas; Jinxiang Dai; Chaitanya R. Badwe; Brunilde Gril; Milica Tešić Mark; Brian D. Dill; Henrik Molina; Haiying Zhang; Alberto Benito-Martin; Linda Bojmar; Yonathan Ararso; Katharine Offer; Quincey LaPlant; Weston Buehring; Huajuan Wang; Xinran Jiang; Tyler M. Lu; Yuan Liu; Joshua K. Sabari; Sandra J. Shin; Navneet Narula; Paula S. Ginter; Vinagolu K. Rajasekhar; John H. Healey; Etienne Meylan; Bruno Costa-Silva; Shizhen Emily Wang; Shahin Rafii; Nasser Khaled Altorki; Charles M. Rudin; David R. Jones; Patricia S. Steeg; Héctor Peinado; Cyrus M. Ghajar; Jacqueline Bromberg; Maria de Sousa; David Pisapia; David Lyden

doi:10.1038/s41556-019-0404-4

Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis

Gonçalo Rodrigues, Ayuko Hoshino, Candia M. Kenific, Irina R. Matei, Loïc Steiner, Daniela Freitas, Han Sang Kim, Peter R. Oxley, Ilana Scandariato, Irene Casanova-Salas, Jinxiang Dai, Chaitanya R. Badwe, Brunilde Gril, Milica Tešić Mark, Brian D. Dill, Henrik Molina, Haiying Zhang, Alberto Benito-Martin, Linda Bojmar, Yonathan ArarsoKatharine Offer, Quincey LaPlant, Weston Buehring, Huajuan Wang, Xinran Jiang, Tyler M. Lu, Yuan Liu, Joshua K. Sabari, Sandra J. Shin, Navneet Narula, Paula S. Ginter, Vinagolu K. Rajasekhar, John H. Healey, Etienne Meylan, Bruno Costa-Silva, Shizhen Emily Wang, Shahin Rafii, Nasser Khaled Altorki, Charles M. Rudin, David R. Jones, Patricia S. Steeg, Héctor Peinado, Cyrus M. Ghajar, Jacqueline Bromberg, Maria de Sousa, David Pisapia, David Lyden

Department of Internal Medicine

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173 Citations (Scopus)

Abstract

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP⁺ exosomes. Moreover, uptake of CEMIP⁺ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Original language	English
Pages (from-to)	1403-1412
Number of pages	10
Journal	Nature Cell Biology
Volume	21
Issue number	11
DOIs	https://doi.org/10.1038/s41556-019-0404-4
Publication status	Published - 2019 Nov 1

Bibliographical note

Funding Information:
We thank M. Ginsberg, G. Marra, P. Raju and T. Milner for reagents and expert advice; L. Nogues Vera, M. Teixeira and S. Grass for help in the laboratory; M. Schaeffer for proofreading; T. Zhang and K. Gyan for help with bioinformatics analysis; L. Cohen-Gould, the MSKCC Molecular Cytology Core Facility and K. Uryu for imaging counselling; T. Miller and F. Fang at the MSKCC Flow cytometry Core Facility, and T. Baumgartner at the Weill Cornell Medicine Flow Cytometry Core, as well as R. Bowman, for expert cell sorting; and the MSKCC Gene Editing and Screening Core Facility for molecular cloning and gene editing advice. We gratefully acknowledge support from the following funding sources: the National Cancer Institute (CA169538 to D.L. and CA232093 to D.L.), the US Department of Defense (W81XWH-13-1-0427 to D.L.), the Breast Cancer Research Foundation (to D.L. and C.M.G.), the Champalimaud Foundation, the Daedalus Fund for Innovation (Weill Cornell Medicine, to D.L.), the Children’s Cancer and Blood Foundation, the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium Foundation, the Nancy C. and Daniel P. Paduano Foundation, the Eileen and James A. Paduano Foundation, the Sohn Foundation, the Hartwell Foundation, the Manning Foundation, the Thompson Foundation, the Malcolm Hewitt Wiener Foundation and the Tortolani Foundation. G.R. has been supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund, and by the Fundação para a Ciência e a Tecnologia from Portugal. A.H. was supported by a Susan Komen Foundation for the Cure Fellowship. H.P. is supported by grants from MINECO (SAF2014-54541-R), Fundación Fero, Asociación Española Contra el Cáncer and Worldwide Cancer Research. C.M.G. is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition’s Artemis Project and the Pink Gene Foundation.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

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Cell Biology

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

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10.1038/s41556-019-0404-4

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Rodrigues, G., Hoshino, A., Kenific, C. M., Matei, I. R., Steiner, L., Freitas, D., Kim, H. S., Oxley, P. R., Scandariato, I., Casanova-Salas, I., Dai, J., Badwe, C. R., Gril, B., Tešić Mark, M., Dill, B. D., Molina, H., Zhang, H., Benito-Martin, A., Bojmar, L., ... Lyden, D. (2019). Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nature Cell Biology, 21(11), 1403-1412. https://doi.org/10.1038/s41556-019-0404-4

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title = "Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis",

abstract = "The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.",

author = "Gon{\c c}alo Rodrigues and Ayuko Hoshino and Kenific, {Candia M.} and Matei, {Irina R.} and Lo{\"i}c Steiner and Daniela Freitas and Kim, {Han Sang} and Oxley, {Peter R.} and Ilana Scandariato and Irene Casanova-Salas and Jinxiang Dai and Badwe, {Chaitanya R.} and Brunilde Gril and {Te{\v s}i{\'c} Mark}, Milica and Dill, {Brian D.} and Henrik Molina and Haiying Zhang and Alberto Benito-Martin and Linda Bojmar and Yonathan Ararso and Katharine Offer and Quincey LaPlant and Weston Buehring and Huajuan Wang and Xinran Jiang and Lu, {Tyler M.} and Yuan Liu and Sabari, {Joshua K.} and Shin, {Sandra J.} and Navneet Narula and Ginter, {Paula S.} and Rajasekhar, {Vinagolu K.} and Healey, {John H.} and Etienne Meylan and Bruno Costa-Silva and Wang, {Shizhen Emily} and Shahin Rafii and Altorki, {Nasser Khaled} and Rudin, {Charles M.} and Jones, {David R.} and Steeg, {Patricia S.} and H{\'e}ctor Peinado and Ghajar, {Cyrus M.} and Jacqueline Bromberg and {de Sousa}, Maria and David Pisapia and David Lyden",

note = "Funding Information: We thank M. Ginsberg, G. Marra, P. Raju and T. Milner for reagents and expert advice; L. Nogues Vera, M. Teixeira and S. Grass for help in the laboratory; M. Schaeffer for proofreading; T. Zhang and K. Gyan for help with bioinformatics analysis; L. Cohen-Gould, the MSKCC Molecular Cytology Core Facility and K. Uryu for imaging counselling; T. Miller and F. Fang at the MSKCC Flow cytometry Core Facility, and T. Baumgartner at the Weill Cornell Medicine Flow Cytometry Core, as well as R. Bowman, for expert cell sorting; and the MSKCC Gene Editing and Screening Core Facility for molecular cloning and gene editing advice. We gratefully acknowledge support from the following funding sources: the National Cancer Institute (CA169538 to D.L. and CA232093 to D.L.), the US Department of Defense (W81XWH-13-1-0427 to D.L.), the Breast Cancer Research Foundation (to D.L. and C.M.G.), the Champalimaud Foundation, the Daedalus Fund for Innovation (Weill Cornell Medicine, to D.L.), the Children{\textquoteright}s Cancer and Blood Foundation, the Pediatric Oncology Experimental Therapeutics Investigator{\textquoteright}s Consortium Foundation, the Nancy C. and Daniel P. Paduano Foundation, the Eileen and James A. Paduano Foundation, the Sohn Foundation, the Hartwell Foundation, the Manning Foundation, the Thompson Foundation, the Malcolm Hewitt Wiener Foundation and the Tortolani Foundation. G.R. has been supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund, and by the Funda{\c c}{\~a}o para a Ci{\^e}ncia e a Tecnologia from Portugal. A.H. was supported by a Susan Komen Foundation for the Cure Fellowship. H.P. is supported by grants from MINECO (SAF2014-54541-R), Fundaci{\'o}n Fero, Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer and Worldwide Cancer Research. C.M.G. is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition{\textquoteright}s Artemis Project and the Pink Gene Foundation. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = nov,

day = "1",

doi = "10.1038/s41556-019-0404-4",

language = "English",

volume = "21",

pages = "1403--1412",

journal = "Nature Cell Biology",

issn = "1465-7392",

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number = "11",

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Rodrigues, G, Hoshino, A, Kenific, CM, Matei, IR, Steiner, L, Freitas, D, Kim, HS, Oxley, PR, Scandariato, I, Casanova-Salas, I, Dai, J, Badwe, CR, Gril, B, Tešić Mark, M, Dill, BD, Molina, H, Zhang, H, Benito-Martin, A, Bojmar, L, Ararso, Y, Offer, K, LaPlant, Q, Buehring, W, Wang, H, Jiang, X, Lu, TM, Liu, Y, Sabari, JK, Shin, SJ, Narula, N, Ginter, PS, Rajasekhar, VK, Healey, JH, Meylan, E, Costa-Silva, B, Wang, SE, Rafii, S, Altorki, NK, Rudin, CM, Jones, DR, Steeg, PS, Peinado, H, Ghajar, CM, Bromberg, J, de Sousa, M, Pisapia, D & Lyden, D 2019, 'Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis', Nature Cell Biology, vol. 21, no. 11, pp. 1403-1412. https://doi.org/10.1038/s41556-019-0404-4

TY - JOUR

T1 - Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis

AU - Rodrigues, Gonçalo

AU - Hoshino, Ayuko

AU - Kenific, Candia M.

AU - Matei, Irina R.

AU - Steiner, Loïc

AU - Freitas, Daniela

AU - Kim, Han Sang

AU - Oxley, Peter R.

AU - Scandariato, Ilana

AU - Casanova-Salas, Irene

AU - Dai, Jinxiang

AU - Badwe, Chaitanya R.

AU - Gril, Brunilde

AU - Tešić Mark, Milica

AU - Dill, Brian D.

AU - Molina, Henrik

AU - Zhang, Haiying

AU - Benito-Martin, Alberto

AU - Bojmar, Linda

AU - Ararso, Yonathan

AU - Offer, Katharine

AU - LaPlant, Quincey

AU - Buehring, Weston

AU - Wang, Huajuan

AU - Jiang, Xinran

AU - Lu, Tyler M.

AU - Liu, Yuan

AU - Sabari, Joshua K.

AU - Shin, Sandra J.

AU - Narula, Navneet

AU - Ginter, Paula S.

AU - Rajasekhar, Vinagolu K.

AU - Healey, John H.

AU - Meylan, Etienne

AU - Costa-Silva, Bruno

AU - Wang, Shizhen Emily

AU - Rafii, Shahin

AU - Altorki, Nasser Khaled

AU - Rudin, Charles M.

AU - Jones, David R.

AU - Steeg, Patricia S.

AU - Peinado, Héctor

AU - Ghajar, Cyrus M.

AU - Bromberg, Jacqueline

AU - de Sousa, Maria

AU - Pisapia, David

AU - Lyden, David

N1 - Funding Information: We thank M. Ginsberg, G. Marra, P. Raju and T. Milner for reagents and expert advice; L. Nogues Vera, M. Teixeira and S. Grass for help in the laboratory; M. Schaeffer for proofreading; T. Zhang and K. Gyan for help with bioinformatics analysis; L. Cohen-Gould, the MSKCC Molecular Cytology Core Facility and K. Uryu for imaging counselling; T. Miller and F. Fang at the MSKCC Flow cytometry Core Facility, and T. Baumgartner at the Weill Cornell Medicine Flow Cytometry Core, as well as R. Bowman, for expert cell sorting; and the MSKCC Gene Editing and Screening Core Facility for molecular cloning and gene editing advice. We gratefully acknowledge support from the following funding sources: the National Cancer Institute (CA169538 to D.L. and CA232093 to D.L.), the US Department of Defense (W81XWH-13-1-0427 to D.L.), the Breast Cancer Research Foundation (to D.L. and C.M.G.), the Champalimaud Foundation, the Daedalus Fund for Innovation (Weill Cornell Medicine, to D.L.), the Children’s Cancer and Blood Foundation, the Pediatric Oncology Experimental Therapeutics Investigator’s Consortium Foundation, the Nancy C. and Daniel P. Paduano Foundation, the Eileen and James A. Paduano Foundation, the Sohn Foundation, the Hartwell Foundation, the Manning Foundation, the Thompson Foundation, the Malcolm Hewitt Wiener Foundation and the Tortolani Foundation. G.R. has been supported by a Peter Oppenheimer Fellowship, awarded by the American Portuguese Biomedical Research Fund, and by the Fundação para a Ciência e a Tecnologia from Portugal. A.H. was supported by a Susan Komen Foundation for the Cure Fellowship. H.P. is supported by grants from MINECO (SAF2014-54541-R), Fundación Fero, Asociación Española Contra el Cáncer and Worldwide Cancer Research. C.M.G. is supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-15-1-0201), the US National Cancer Institute (CA193461-01), the National Breast Cancer Coalition’s Artemis Project and the Pink Gene Foundation. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

AB - The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

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VL - 21

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JO - Nature Cell Biology

JF - Nature Cell Biology

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ER -

Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis

Abstract

Bibliographical note

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