Over 90% of breast cancer mortality is caused by metastasis rather than primary tumors. The majority of metastases occur to bone. In the late stage, bone metastases often cause bone fractures and spine compression, a result of dramatic bone resorption caused by cancer cells. The bone resorption will release growth factors stored in the bone matrix and foster the growth of cancer cells, thus forming a vicious cycle. Drugs that are used to treat bone metastasis target on the bone absorbing cells rather than cancer cells can only partially slow down tumor progression. On the other hand, there are often years to decades of latency after primary tumor removal and before bone metastasis detection, suggesting that cancer cells may exist in an undetectable and indolent status for a long time, without activating the bone resorption. We reasoned that if we can learn how the early phase bone metastases survive and maintain their potential to progress, we may be able to eradicate these cells before they become capable to initiate the vicious cycle and prevent overt bone metastasis.

My training in the Zhang Lab is highly relevant for my career goal. Dr. Zhang is an outstanding junior Principal Investigator. He has been working on breast cancer metastasis, especially bone metastasis, for over 7 years. Under his supervision, we have systematically examined the microenvironment of breast cancer cells that have just disseminated to the bone marrow. We found that mesenchymal stem cells (MSCs), the precursor of several types of bone cells, preferentially form direct contact with cancer cells. A series of subsequent experiments demonstrated that the presence of MSCs actually boosts the ability of cancer cells to survive and progress, even though some of them are originally unable to do so. We also made an interesting observation that MSCs and cancer cells tend to form very organized structure when mixed together. Thus, it seems that direct contact between MSCs and cancer cells is required for bone metastasis progression. We went on to uncover two candidate mediators of MSC-cancer interaction, namely Eph receptor and their interacting ephrin ligands. These genes represent novel therapeutic targets that may be used to eradicate bone metastasis before it becomes incurable.

Most breast cancer survivors remain endangered by metastatic recurrences. The risk peaks at 2 years, but maintains at a significant level for up to 15 years. Current adjuvant therapies are not sufficient to prevent recurrences. Thus, our research will likely to benefit the vast majority of breast cancer patients that appear tumor-free but are under risk of recurrences. The molecules that may mediate MSC-cancer interaction are promising therapeutic targets. Fortuitously, drugs have already been invented against these molecules. As a result, functional validation and preclinical tests of these molecules will potentially generate swift clinical impact. The projected time to achieve patient-related outcomes for these targets will be within 3-5 years after this project finishes. We will also take unbiased approaches to discover other targets, which would then be subject to systematic investigation and take longer time before reaching the clinical outcomes.

This proposed research and my postdoctoral training will take place in the Lester and Sue Smith Breast Center (Breast Center) at Baylor College of Medicine (BCM), which is a highly collaborative and multidisciplinary environment with basic science, translational, and clinical research well-integrated. The dedication toward postdoctoral training here is reinforced by the bi-weekly Research and Development workshops, journal club series, weekly breast cancer seminars, and the annual Breast Center Retreat, which allows trainees to showcase their latest research developments to various institutions around the Texas Medical Center. In addition to the training provided by the Breast Center, the department of Molecular and Cellular Biology (MCB) holds its annual postdoctoral symposium, a weekly seminar series with a diverse pool of seminar speakers from all areas in biology. All of these events create the perfect environment in which to not only present my research to my peers and faculty, but to receive valuable feedback, which will only advance my research to a higher level. Finally, I will maintain a routine interaction with Dr. Zhang through weekly individual meetings and lab meetings. Drs. Jeffrey Rosen and Yi Li will be my co-mentors and will meet me every 3 months. Moreover, the Zhang Lab participates in joint lab meetings among the labs of Drs. Jeffrey Rosen, Yi Li, Mike Lewis, Li Xin, and Keith Chan. Therefore, I have complete confidence that these experiences will allow me to become a productive breast cancer researcher as my career develops.