Department of Molecular and Cellular Biology
Lester and Sue Smith Breast Center
Baylor College of Medicine
Dr. Zhang aims to understand how slowly-dividing or dormant cancer cells resist conventional adjuvant therapies particularly in bones, the organ most frequently affected by breast cancer metastases. His experiments during the last grant cycle identified two estrogen receptor-positive (ER+) cancer cell models that exhibit indolence or dormancy when placed to the bone and bone marrow. Interestingly, extraction and fragmentation of the cancer-bearing bones do not significant alter the behaviors of cancer cells inside of the bones, making it possible to study metastatic growth and therapeutic responses of cancer cells in bone fragments in tissue culture. This system is referred to as “Bone-In-Culture Array,” or BICA. Dr. Zhang has also done further experiments to understand how cancer cells exist in intact bones and why they are so tightly associated with bones even after the fragmentation. He found that cancer cells are fully encompassed by bone cells (osteoblasts) to the extent that one has to “dissolve” the bone to separate cancer cells. This finding demonstrates for the first time a specialized microenvironment niche of the microscopic metastases in the bone. It also provides support and justification for the usage of BICA to investigate therapeutic responses of cancer cells. Furthermore, Dr. Zhang has also performed preliminary studies applying widely-used anti-estrogen and anti-HER2 drugs to BICA, and demonstrated the feasibility of using it as a novel platform for pre-clinical studies. Dr. Zhang will continue to develop BICA and use it to investigate bone-specific mechanisms of resistance to anti-hormonal therapies.
Dr. Zhang aims to understand how slowly-dividing or dormant cancer cells resist conventional adjuvant therapies particularly in bones, the organ most frequently affected by breast cancer metastases. His previous work established a novel experimental platform named “Bone-In-Culture Array”, or BICA, which allows his team to swiftly examine effects of multiple drugs on cancer cells in the context of bone. Briefly, this system is based on fragmentation of bones of laboratory models that are loaded with cancer cells through intra-iliac artery injection. Dr. Zhang has shown in previous reports that cancer cells in BICA retain most of the cell-biological features that they exhibit in intact bones. In the past three months, he and his colleagues have achieved three things. First, they systematically compared the bone cells surrounding cancer cells in BICA to those in intact bones, and confirmed that the composition of the environment of bone metastasis is largely maintained in BICA. This is important because it further justifies that BICA can be used as a valid surrogate of bone metastases in laboratory models. Second, they examined the therapeutic responses of cancer cells in BICA to several drugs, and compared the results to the responses of the same cancer cells in culture. The results of these experiments illustrate that the bone environment does influence the effects of drugs. While some drugs may not work as well because of the protection effects of bone cells, others are actually more efficient. These experiments demonstrate that the bone context alter the drug sensitivity of cancer cells, and BICA is likely to reveal the alteration and underlying mechanisms, which would not be possible using conventional cell cultures. Finally, the researchers have successfully validated the effects of a neutralizing antibody on cancer cells in BICA, thereby extending the potential utility of BICA from small molecule inhibitors to antibody-based interventions. Overall, these new results have significantly moved the project forward.
Dr. Xiang (Shawn) Zhang is an Assistant Professor at Lester and Sue Smith Breast Center of Baylor College of Medicine. He received his doctoral degree from Columbia University in the City of New York. In his graduate work in Dr. Lawrence Chasin’s laboratory, Dr. Zhang focused on the genomics of pre-mRNA splicing, and gained training in bioinformatics and molecular biology. He then joined Dr. Joan Massague’s laboratory at Memorial Sloan-Kettering Cancer Center, where he switched to the field of cancer metastasis. Dr. Zhang made several findings using an integrative strategy combining cancer genomics and experimental metastasis approaches. Specifically, he discovered a bone-specific pro-survival role of Src kinase in metastasis. He also tied Src activity to the risk of bone metastasis in clinical microarray data. In a further study pursuing the mechanism of Src activation in both primary tumors and bone metastases, he found a critical role of microenvironment in driving tumor evolution toward a Src-positive status through a clonal selection process.
Dr. Zhang was named McNair Scholar in 2011, an award established by the McNair Foundation to provide start-up funds for distinguished scientists joining Baylor College of Medicine. He is also an awardee of the K99/R00 Pathways to Independence Grant from National Cancer Institute. In his own laboratory at Baylor College of Medicine, Dr. Zhang continues to investigate biological mechanisms and therapeutic strategies of breast cancer metastasis. In particular, his team has developed and adopted several unique techniques and protocols to investigate micrometastases in bone. His long-term goals are to eradicate latent cancer cells in distant organs, and to reduce the incidence of overt metastases.