Metastasis accounts for nearly all breast cancer-related deaths. Bone is the organ most frequently affected by breast cancer. In the clinically significant stage, bone metastasis is driven by a vicious cycle between cancer cells and osteoclasts (bone-resorbing cells). Our knowledge of this vicious cycle has vastly increased in recent years, and therapies targeting osteoclasts can often significantly delay the progression of disease. However, bone metastases still remain incurable. On the other hand, there is often a latency of years to decades before bone metastases become clinically detectable, suggesting that residual cancer cells can exist in bone or bone marrow for a protracted period of time without activating osteoclasts. We set out to discover osteoclast- independent mechanisms in early-stage bone colonization before the onset of the vicious cycle. Our prelimi- nary data demonstrated that osteoblasts (bone-making cells) and their precursor cells constitute the microenvi- ronment niche of microscopic bone metastases. The direct cell-cell contact between cancer cells and the """"""""os- teoblastic niche"""""""" is crucial for their proliferation. Further studies indicated that the re-activation of the mTOR pathway is a hallmark of bone metastasis initiation. We also obtained preliminary evidence suggesting that the activation of mTOR is mediated by the formation of adhesion junctions (AJs) between cancer cells and niche cells. Based on these findings, we hypothesize that the osteoblastic niche facilitates bone metastasis progres- sion of breast cancer from single cells to multi-cell micrometastases by augmenting the activity of the mTOR pathway, possibly through signaling downstream of AJ complexes. To test this hypothesis, we will pursue two specific aims: 1) to determine the mechanism mediating the crosstalk between cancer cells and the osteo- blastic niche, which entails direct cell-cell contact and leads to the activation of mTOR signaling, and 2) to iden- tify the downstream effectors of mTOR that drive metastasis initiation. Our work is innovative and feasible be- cause it employs a novel technique that selectively delivers cancer cells into hind limb bones via the circulation. This approach enables swift inspection and robust quantification of bone micrometastases at a single-cell reso- lution, yet avoids caveats of other conventional approaches. Application of this technique to several cancer models resulted in indolent or dormant bone metastases that mimic human diseases. We will use this ap- proach for xenograft and syngeneic transplantation of human and mouse cancer cells, respectively, and inves- tigate the roles of AJs, the mTOR complexes, and their related signaling molecules in bone metastasis initia- tion. In addition, we also invented a 3D co-culture system that faithfully recapitulates many features of cancer- niche interaction, which will facilitate the dissection of molecular mechanisms and accelerate our examination of candidate mediators. The fulfillment of these aims will enable the design of targeted therapies to suppress or eradicate latent tumor cells, and reduce the incidence of overt bone metastasis-related symptoms and mortality.

Public Health Relevance

Bone metastases that occur years to decades after surgical removal of primary tumors are a clinical challenge. It remains poorly understood how cancer cells resume aggressive growth after a long period of indolence or dormancy. The studies proposed herein will advance our understanding of how bone metastases progress from single cells to multi-cell lesions, and will uncover potential therapeutic targets for the prevention of overt bone metastases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Wang, Hai; Tian, Lin; Liu, Jun et al. (2018) The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability. Cancer Cell 34:823-839.e7
Janghorban, Mahnaz; Xin, Li; Rosen, Jeffrey M et al. (2018) Notch Signaling as a Regulator of the Tumor Immune Response: To Target or Not To Target? Front Immunol 9:1649
Tian, Lin; Goldstein, Amit; Wang, Hai et al. (2017) Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544:250-254
Welte, Thomas; Zhang, Xiang H-F; Rosen, Jeffrey M (2017) Repurposing Antiestrogens for Tumor Immunotherapy. Cancer Discov 7:17-19
Wang, Hai; Tian, Lin; Goldstein, Amit et al. (2017) Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies. Nat Commun 8:15045
Bado, I; Gugala, Z; Fuqua, S A W et al. (2017) Estrogen receptors in breast and bone: from virtue of remodeling to vileness of metastasis. Oncogene 36:4527-4537
Yu, Cuijuan; Wang, Hai; Muscarella, Aaron et al. (2016) Intra-iliac Artery Injection for Efficient and Selective Modeling of Microscopic Bone Metastasis. J Vis Exp :
Kim, Ik Sun; Zhang, Xiang H-F (2016) One microenvironment does not fit all: heterogeneity beyond cancer cells. Cancer Metastasis Rev 35:601-629
Welte, Thomas; Kim, Ik Sun; Tian, Lin et al. (2016) Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat Cell Biol 18:632-44
Welte, Thomas; Zhang, Xiang H-F (2015) Interleukin-17 Could Promote Breast Cancer Progression at Several Stages of the Disease. Mediators Inflamm 2015:804347

Showing the most recent 10 out of 12 publications