PT - JOURNAL ARTICLE AU - Ana Rita Nobre AU - Emma Risson AU - Deepak K. Singh AU - Julie Di Martino AU - Julie F. Cheung AU - Jiapeng Wang AU - John Johnson AU - Hege G. Russnes AU - Jose Javier Bravo-Cordero AU - Alexander Birbrair AU - Bjorn Naume AU - Mohamad Azhar AU - Paul S. Frenette AU - Julio A. Aguirre-Ghiso TI - NG2<sup>+</sup>/Nestin<sup>+</sup> mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2 AID - 10.1101/2020.10.22.349514 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.10.22.349514 4099 - http://biorxiv.org/content/early/2020/10/22/2020.10.22.349514.short 4100 - http://biorxiv.org/content/early/2020/10/22/2020.10.22.349514.full AB - 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 StatementJ.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.