Nobre Ana Rita, Risson Emma, Singh Deepak K, Di Martino Julie S, Cheung Julie F, Wang Jiapeng, Johnson John, Russnes Hege G, Bravo-Cordero Jose Javier, Birbrair Alexander, Naume Bjorn, Azhar Mohamad, Frenette Paul S, Aguirre-Ghiso Julio A
Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Department of Oncological Sciences, Black Family Stem Cell Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
Nat Cancer. 2021 Mar;2(3):327-339. doi: 10.1038/s43018-021-00179-8. Epub 2021 Mar 11.
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 p38-kinase result in p27 induction. Genetic depletion of MSCs or conditional knock-out of TGFβ2 in MSCs using an NG2-Cre 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.
在骨髓（BM）微环境中，乳腺癌（BC）播散肿瘤细胞（DTCs）可保持休眠数十年，NG2/巢蛋白间充质干细胞（MSCs）促进造血干细胞静止。在此，我们发现小动脉周围驻留的BM-NG2/巢蛋白MSCs也能指导BC DTCs进入休眠状态。NG2/巢蛋白MSCs产生转化生长因子β2（TGFβ2）和骨形态发生蛋白7（BMP7），并激活一条依赖于转化生长因子β受体III（TGFBRIII）和骨形态发生蛋白受体II（BMPRII）的静止通路，这会导致p38激酶诱导p27。使用NG2-Cre驱动因子对MSCs进行基因缺失或条件性敲除MSCs中的TGFβ2，会导致原本休眠的p27/Ki67 DTCs发生骨转移生长。此外，无全身复发的雌激素受体（ER）阳性BC患者的骨髓中TGFβ2和BMP7的检测频率更高。我们的结果直接证明了造血干细胞休眠微环境控制着BC DTCs的休眠，并表明影响NG2/巢蛋白MSCs微环境稳态的衰老或外在因素可能导致休眠中断和BC骨复发。
