2017年度秋季学期学术系列讲座之十
题目：Understanding cancer metastasis and the microenvironment in the age of single-cell biology
讲座人：Zena Werb, Ph.D.
Professor and Vice-Chair
Department of Anatomy,
University of California, San Francisco
时间：2017年11月24日（星期五），13:00-14:30
地点：威廉希尔邓祐才报告厅 
主持人：李湘盈
摘要：
Metastasis is the major cause of poor outcome in breast cancer. Understanding the processes involved in metastasis is critical for developing new preventative and therapeutic strategies. The cancer cells within tumors are heterogeneous and can have properties as divergent as self-renewal, tumor initiation and repopulation potential, dormancy, evasion of cell death and metastasis. Cancer-initiating cells reside in niches as is the case for normal tissue stem cells. Proliferation and differentiation are deregulated in these niches. We have studied normal breast epithelium by single-cell RNA sequencing as a powerful strategy to identify cell types and states in a given population of cells. We discovered previously unrealized expression patterns of known epithelial markers as well as identifying new markers and developed an in silico pathway for human mammary epithelial development. We then exploited patient-derived xenograft (PDX) models of human breast cancer to analyze metastatic cells in peripheral tissues and to characterize of the metastatic niche. We developed a highly sensitive FACS-based assay to isolate metastatic cells from PDX models, which allowed us to enumerate the human metastatic cells in mouse peripheral tissues as well as to isolate the mouse stromal and inflammatory cells. When we compared gene signatures by RNA-seq in metastatic cells and stromal cells we observed that inflammatory microenvironment of metastatic sites was distinct from that of the parental tumor and the normal tissue, even before metastasis takes hold. At the single-cell level early stage metastatic cells possessed a distinct stem-like gene expression signature with increased expression of stem cell, EMT, pro-survival, and dormancy-associated genes. In contrast, metastatic cells from macro-metastases were similar to primary tumor cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. These findings support a hierarchical model for metastasis, where metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease. Thus, metastatic niches may be sensitive to novel therapies and targeting them may prevent metastatic disease from advancing and presenting a poor outcome. (Funded by the National Cancer Institute)
参考文献：
Casbon, A.-J., D. Reynaud, C. Park, E. Khuc, D. D. Gan, K. Schepers, E. Passegué & Z. Werb (2015). Tumors reprogram early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl. Acad. Sci. U.S.A. 112:E566-E575. 
Lawson, D. A., N. Bhakta, K. Kessenbrock, K. Prummel, Y. Yu, K. Takai, A. Zhou, H. Eyob, S. Balakrishnan, C.-Y. Wang, P. Yaswen, A. Goga & Z. Werb (2015). Single-cell analysis reveals a stem cell program in early human metastatic breast cancer cells. Nature. 526:131–135.
Plaks, V., N. Kong & Z. Werb (2015). The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16: 225-238. 
Takai, K., A.  Le, V. M. Weaver & Z. Werb (2016). Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget. 7:82889-82901. 
Hagerland, C. & Z. Werb (2016). Neutrophils: critical components in experimental animal models of cancer. Semin. Immunol. 28: 197-204.
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