Bone marrow NG2⁺/Nestin⁺ mesenchymal stem cells drive DTC dormancy via TGFβ2

In the bone marrow (BM) microenvironment, where breast cancer (BC) disseminated tumour 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 TGFβ2 and BMP7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, which via p38-kinase result in p27 induction. Genetic depletion of MSCs or conditional knock-out of TGFβ2 in MSCs using an NG2-Cre^ER driver led to bone metastatic outgrowth of otherwise dormant p27⁺/Ki67^- DTCs. Also ER⁺ BC patients without systemic recurrence displayed higher frequency of TGFβ2 and BMP7 detection in the BM. Our results provide a direct proof that HSC 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.