NG2/Nestin mesenchymal stem cells dictate DTC dormancy in the bone marrow through TGFβ2
bioRxiv, ISSN: 2692-8205
2020
- 4Citations
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- Citations4
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- CrossRef4
Article Description
In the bone marrow (BM) microenvironment, NG2/Nestin mesenchymal stem cells (MSCs) promote hematopoietic stem cell (HSC) quiescence. Importantly, the BM can also harbour disseminated tumour cells (DTCs) from multiple cancers, which, like HSCs, can remain dormant. The BM signals are so growth-restrictive that dormant BM DTCs can persist for years to decades only to awaken and fuel lethal metastasis. 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.
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