Bone marrow NG2+/Nestin+ mesenchymal stem cells drive DTC dormancy via TGF-β2

Ana Rita Nobre; Emma Risson; Deepak K. Singh; Julie S. 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

doi:10.1038/s43018-021-00179-8

Bone marrow NG2⁺/Nestin⁺ mesenchymal stem cells drive DTC dormancy via TGF-β2

Ana Rita Nobre, Emma Risson, Deepak K. Singh, Julie S. 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

Medicine

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

62 Scopus citations

Abstract

In the bone marrow (BM) microenvironment, where breast cancer (BC)-disseminated tumor cells (DTCs) can remain dormant for decades, NG2⁺/Nestin⁺ mesenchymal stem cells (MSCs) promote hematopoietic stem cell quiescence. Here we reveal that periarteriolar BM-resident NG2⁺/Nestin⁺ MSCs can also instruct BC DTCs to enter dormancy. NG2⁺/Nestin⁺ MSCs produce transforming growth factor (TGF)-β2 and bone morphogenetic protein (BMP)7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase, results in p27 induction. Genetic depletion of MSCs or conditional knockout of TGF-β2 in MSCs using an NG2-Cre^ER driver led to bone metastatic outgrowth of otherwise dormant p27⁺/Ki67⁻ DTCs. Also, patients with estrogen receptor-positive BC without systemic recurrence displayed higher frequency of TGF-β2 and BMP7 detection in the BM. Our results provide direct proof that hematopoietic stem cell dormancy niches control BC DTC dormancy and suggest that aging or extrinsic factors that affect the NG2⁺/Nestin⁺ MSC niche homeostasis may result in a break from dormancy and BC bone relapse.

Original language	English (US)
Pages (from-to)	327-339
Number of pages	13
Journal	Nature Cancer
Volume	2
Issue number	3
DOIs	https://doi.org/10.1038/s43018-021-00179-8
State	Published - Mar 2021

ASJC Scopus subject areas

Oncology
Cancer Research
General Medicine

UN SDGs

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

Access to Document

10.1038/s43018-021-00179-8

Cite this

Nobre, A. R., Risson, E., Singh, D. K., Di Martino, J. S., Cheung, J. F., Wang, J., Johnson, J., Russnes, H. G., Bravo-Cordero, J. J., Birbrair, A., Naume, B., Azhar, M., Frenette, P. S., & Aguirre-Ghiso, J. A. (2021). Bone marrow NG2⁺/Nestin⁺ mesenchymal stem cells drive DTC dormancy via TGF-β2. Nature Cancer, 2(3), 327-339. https://doi.org/10.1038/s43018-021-00179-8

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abstract = "In the bone marrow (BM) microenvironment, where breast cancer (BC)-disseminated tumor cells (DTCs) can remain dormant for decades, NG2+/Nestin+ mesenchymal stem cells (MSCs) promote hematopoietic stem cell quiescence. Here we reveal that periarteriolar BM-resident NG2+/Nestin+ MSCs can also instruct BC DTCs to enter dormancy. NG2+/Nestin+ MSCs produce transforming growth factor (TGF)-β2 and bone morphogenetic protein (BMP)7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase, results in p27 induction. Genetic depletion of MSCs or conditional knockout of TGF-β2 in MSCs using an NG2-CreER driver led to bone metastatic outgrowth of otherwise dormant p27+/Ki67− DTCs. Also, patients with estrogen receptor-positive BC without systemic recurrence displayed higher frequency of TGF-β2 and BMP7 detection in the BM. Our results provide direct proof that hematopoietic stem cell dormancy niches control BC DTC dormancy and suggest that aging or extrinsic factors that affect the NG2+/Nestin+ MSC niche homeostasis may result in a break from dormancy and BC bone relapse.",

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