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NG2+/Nestin+ mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2

View ORCID ProfileAna Rita Nobre, View ORCID ProfileEmma Risson, Deepak K. Singh, Julie Di Martino, Julie F. Cheung, Jiapeng Wang, John Johnson, Hege G. Russnes, Jose Javier Bravo-Cordero, Alexander Birbrair, Bjorn Naume, Mohamad Azhar, Paul S. Frenette, View ORCID ProfileJulio A. Aguirre-Ghiso
doi: https://doi.org/10.1101/2020.10.22.349514
Ana Rita Nobre
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal
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Emma Risson
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Université de Lyon, F-69000, Lyon, France
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Deepak K. Singh
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Julie Di Martino
4Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Julie F. Cheung
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Jiapeng Wang
5Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
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John Johnson
5Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
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Hege G. Russnes
6Oslo University Hospital, Department of Oncology, Division of Surgery and Cancer Medicine, Oslo, Norway
7Oslo University Hospital, Department of Pathology, Division of Laboratory Medicine, Oslo, Norway
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Jose Javier Bravo-Cordero
4Department of Medicine, Division of Hematology and Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Alexander Birbrair
8Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA
9Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Brazil
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Bjorn Naume
10Oslo University Hospital, Department of Oncology, Division of Cancer Medicine, Oslo, Norway
11Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Mohamad Azhar
5Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
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Paul S. Frenette
8Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, USA
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Julio A. Aguirre-Ghiso
1Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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  • ORCID record for Julio A. Aguirre-Ghiso
  • For correspondence: julio.aguirre-ghiso@mssm.edu
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Abstract

In the bone marrow (BM) microenvironment, NG2+/Nestin+ mesenchymal stem cells (MSCs) promote hematopoietic stem cell (HSC) quiescence1,2. Importantly, the BM can also harbour disseminated tumour cells (DTCs) from multiple cancers, which, like HSCs, can remain dormant3. The BM signals are so growth-restrictive that dormant BM DTCs can persist for years to decades only to awaken and fuel lethal metastasis3–10. The mechanisms and niche components regulating DTC dormancy remain largely unknown. Here, we reveal that periarteriolar BM-resident NG2+/Nestin+ MSCs can instruct breast cancer (BC) DTCs to enter dormancy. NG2+/Nestin+ MSCs produce TGFβ2 and BMP7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase result in p27-CDK inhibitor induction. Importantly, genetic depletion of the NG2+/Nestin+ MSCs or conditional knock-out of TGFβ2 in the NG2+/Nestin+ MSCs led to awakening and bone metastatic expansion of otherwise dormant p27+/Ki67− DTCs. Our results provide a direct proof that HSC dormancy niches control BC DTC dormancy. Given that aged NG2+/Nestin+ MSCs can lose homeostatic control of HSC dormancy, our results suggest that aging or extrinsic factors that affect the NG2+/Nestin+ MSC niche may result in a break from dormancy and BC bone relapse.

Competing Interest Statement

J.A.A.-G. is a scientific co-founder of, scientific advisory board member and equity owner in HiberCell and receives financial compensation as a consultant for HiberCell, a Mount Sinai spin-off company focused on the research and development of therapeutics that prevent or delay the recurrence of cancer.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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NG2+/Nestin+ mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2
Ana Rita Nobre, Emma Risson, Deepak K. Singh, Julie Di Martino, Julie F. Cheung, Jiapeng Wang, John Johnson, Hege G. Russnes, Jose Javier Bravo-Cordero, Alexander Birbrair, Bjorn Naume, Mohamad Azhar, Paul S. Frenette, Julio A. Aguirre-Ghiso
bioRxiv 2020.10.22.349514; doi: https://doi.org/10.1101/2020.10.22.349514
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NG2+/Nestin+ mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2
Ana Rita Nobre, Emma Risson, Deepak K. Singh, Julie Di Martino, Julie F. Cheung, Jiapeng Wang, John Johnson, Hege G. Russnes, Jose Javier Bravo-Cordero, Alexander Birbrair, Bjorn Naume, Mohamad Azhar, Paul S. Frenette, Julio A. Aguirre-Ghiso
bioRxiv 2020.10.22.349514; doi: https://doi.org/10.1101/2020.10.22.349514

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