Metastasis, the spread of cancer cells from the primary tumor to distant organs, is the most dreadful development of neoplastic diseases. Although metastasis contributes to over 90% of human cancer mortality, the molecular mechanism of this process remains largely unknown. Our laboratory applies a multidisciplinary approach to analyze the molecular basis of cancer metastasis, combining molecular biology and genomics tools with animal models and advanced in vivo imaging technologies.

Identification and functional characterization of tissue-specific metastasis genes.

Each type of cancer has a specific pattern of metastatic distributions. For example, breast cancer metastases can emerge in a variety of organs including bone, lung, lymph node and brain. In contrast, colorectal cancer frequently metastasizes to liver but rarely to bone. What determines the metastasis tissue tropism at the molecular level still remains a daunting challenge to cancer biologists. We have previously established a functional genomics strategy to identify tissue-specific metastasis genes. Human cancer cells were injected into the systemic blood circulation of immunodeficient mice. After the emergence of metastases in different target organs, sub-population of tumor cells with different metastatic ability and tissue-tropism were isolated. Candidate tissue-specific metastasis genes were identified by genomic profiling of these cells. Using this approach, we identified a breast cancer bone metastasis gene profile which contains known metastasis mediators such as the chemokine receptor CXCR4, as well as many genes that had not been implicated in metastasis previously. These genes regulate cell shape and migration, interactions with extracellular matrix and stroma, angiogenesis, and bone metabolism. Subsequent functional testing and clinical correlation studies validated the importance of these genes in human breast cancer bone metastasis. We are now applying similar strategies to analyze other types of cancer and other metastasis tissue tropisms. Using a series of in vivo and in vitro functional assays, candidate metastasis genes will be characterized for their roles in the multi-step metastasis cascade. We are also investigating the genetic and epigenetic events that lead to the aberrant expression of metastasis genes in highly metastatic cells. The ultimate goal of this line of research is to enable targeted therapeutics against the metastatic spread of cancer.

Molecular network of tumor-stroma interactions during metastasis.

The complex, dynamic interactions between tumor cells and the surrounding host microenvironment play a key role in promoting metastatic progression. To thrive in a secondary organ, cancer cells often utilize or alter the normal physiological functions of stroma cells. On the other hand, stroma microenvionment not only serves as a passive soil for the seeding and growth of metastatic cells, but also plays an active role in influencing the metastatic behavior of tumor cells. For example, bone matrix has abundant storage of cytokine TGFb, which has a profound growth inhibitory effect on normal epithelial cells and early stage tumor cells. However, this growth inhibitory effect is often selectively lost during tumor progression, and late stage breast cancer cells instead acquire the ability to respond to TGFb with enhanced metastasis potential. The release of TGFb from bone matrix during osteolytic bone metastasis activates the transcription of two bone metastasis genes, IL11 and CTGF, in cancer cells, further enhancing their metastatic behavior. One focus of our laboratory is to study the influence of growth factors or cytokines released from metastatic cancer cell on the cellular behaviors of stroma cells. With the establishment of a comprehensive inventory of metastasis genes, we will use bioinformatics tools to identify common signaling and transcriptional regulation pathways that influence metastasis gene functions. The role of these pathways in the tumor-stroma crosstalk during metastasis will be investigated. Delineation of the molecular interaction network between metastatic tumor cells and the surrounding target organ microenvironment will provide new insights about how metastatic growth is initiated and maintained.

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