| Literature DB >> 34993493 |
Ana Rita Nobre1,2, Emma Risson1,3, Deepak K Singh1, Julie S Di Martino4, Julie F Cheung1, Jiapeng Wang5, John Johnson5, Hege G Russnes6,7, Jose Javier Bravo-Cordero4, Alexander Birbrair8,9, Bjorn Naume10,11, Mohamad Azhar5, Paul S Frenette8, Julio A Aguirre-Ghiso12.
Abstract
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-CreER 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.Entities:
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Year: 2021 PMID： 34993493 PMCID： PMC8730384 DOI： 10.1038/s43018-021-00179-8
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347