Posted July 21, 2015
Hai Wang, Ph.D., Baylor College of Medicine
Breast cancer mortality is highly associated with cancer metastases, which frequently appear in bone. Vicious interactions between cancer cells and the cells that build and break down bone are the driving force behind the progression of bone metastases during late stages. Current therapies targeting these cellular interactions limit tumor progression but ultimately fail to improve patient survival. Little is known about the early stages of cancer metastasis, when microscopic metastases can remain quiescent for long periods of time before growing into detectable tumors. The eradication of micrometastases represents an important therapeutic opportunity for the prevention of cancerous bone lesions.
Dr. Hai Wang, with funding from an FY12 BCRP Postdoctoral Award and under the mentorship of Dr. Xiang Zhang, developed a mouse model to examine how breast cancer cells survive and colonize in bone during early stages of metastasis. Bone samples obtained from these mice revealed that micrometastases reside in a specific niche and preferentially associate with osteogenic (bone-forming) cells. Dr. Wang found that cancer and resident niche cells made direct contact through the E-cadherin proteins on the cancer cell and the N-cadherin proteins on the niche cell, leading to the investigation of a role for cell-to-cell connections called heterotypic adherins junctions (hAJs) in the support of tumor progression within this niche. Dr. Wang observed that the spread of breast cancer metastases can be reduced by disruption of hAJs, suggesting that hAJ formation may be a critical step in the early colonization of cancer cells. Using a 3D cell culture model, Dr. Wang discovered that the presence of bone-forming osteoblasts promoted the survival and proliferation of breast cancer cells, potentially through the activation of the protein kinase mTOR. Dr. Wang made the important discovery that activation of the mTOR signaling pathway is associated with the progression from single cells to osteolytic metastases.
Dr. Wang's research provides a foundation for the clinical development of novel therapies that might specially target the mTOR signaling pathway or hAJs. This work could illuminate new therapeutic avenues for the prevention of breast cancer metastases, as well as potential strategies to protect cancer patients who appear tumor-free yet are still at high risk for metastatic recurrences. Additional information regarding Dr. Wang's research can be found in the February 2015 issue of Cancer Cell.
Wang H, Yu C, Gao X, et al. 2015. The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27(2): 193-210.