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

Abstract

In the bone marrow (BM) microenvironment, NG2⁺/Nestin⁺ mesenchymal stem cells (MSCs) promote hematopoietic stem cell (HSC) quiescence^1,2. 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 metastasis^3–10. 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.