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

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.

doi:10.1101/2020.10.22.349514

bioRxiv · 10.1101/2020.10.22.349514

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

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.

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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 TGF{beta}2 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 TGF{beta}2 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.

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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.. 2020-10-22. NG2+/Nestin+ mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2. https://doi.org/10.1101/2020.10.22.349514

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