The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells.
The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells.
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DOI：
10.1016/j.ccell.2014.11.017
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发表时间：
2015-02-09
期刊：
影响因子：
50.3
通讯作者：
Zhang XH
中科院分区：
文献类型：
--
作者：
Wang H;Yu C;Gao X;Welte T;Muscarella AM;Tian L;Zhao H;Zhao Z;Du S;Tao J;Lee B;Westbrook TF;Wong ST;Jin X;Rosen JM;Osborne CK;Zhang XH
乳腺癌骨微转移在进展为明显病变之前可以保持无症状数年。这一过程的生物学原理，包括微环境生态位和支持途径，尚不清楚。我们发现骨微转移主要存在于表现出成骨特征的生态位中。生态位相互作用由异型粘附连接 (hAJ) 介导，涉及癌症来源的 E-钙粘蛋白和成骨 N-钙粘蛋白，其破坏会消除生态位赋予的优势。我们进一步阐明 hAJ 激活癌细胞中的 mTOR 通路，从而驱动从单细胞到微转移的进展。人类数据集分析支持 AJ 和 mTOR 通路在骨定植中的作用。我们的研究阐明了骨定植的起始，并提供了阻止溶骨性转移进展的潜在治疗靶点。在晚期，乳腺癌骨转移是由癌细胞、成骨细胞和破骨细胞之间的旁分泌串扰驱动的，构成恶性溶骨循环。目前针对这一过程的疗法限制了肿瘤进展，但不能提高患者的生存率。另一方面，骨微转移在激活恶性循环之前可能会保持惰性数年，从而提供了预防大转移的治疗机会。在这里，我们表明骨定植是在表现出活跃的成骨作用的微环境生态位中启动的。癌细胞和成骨细胞形成异型粘附连接，增强 mTOR 活性并在骨质溶解之前驱动早期骨定植。这些结果揭示了成骨和微转移之间的密切联系，并提出了预防骨大转移的潜在治疗靶点。
Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases.
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影响因子：
11.2
作者：
Liu S;Ginestier C;Ou SJ;Clouthier SG;Patel SH;Monville F;Korkaya H;Heath A;Dutcher J;Kleer CG;Jung Y;Dontu G;Taichman R;Wicha MS
通讯作者：
Wicha MS
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
3.7
作者：
LYNCH, MP;STEIN, JL;LIAN, JB
通讯作者：
LIAN, JB
DOI：
10.1073/pnas.2234372100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Bakewell, SJ;Nestor, P;Weilbaecher, KN
通讯作者：
Weilbaecher, KN
影响因子：
50.3
作者：
Kang, YB;Siegel, PM;Massagué, J
通讯作者：
Massagué, J