Understanding cancer metastasis and the microenvironment in the age of single-cell biology

Research Seminar
Title: Understanding cancer metastasis and the microenvironment in the age of single-cell biology
Speaker: Zena Werb, Ph.D.
Professor and Vice-Chair
Department of Anatomy,
University of California, San Francisco
Time: 13:00-14:30, Nov. 24, 2017
Location: Youcai Deng Hall，School of Life Sciences（太阳成集团tyc7111cc邓祐才报告厅）
Abstract：
Almost all activities inside our cells are carried out by macromolecular complexes. Defects in these protein and complexes can cause malfunction and diseases. My research focuses on elucidating the structures and mechanisms of large macromolecular complexes, especially those involved in DNA processing, such as transcription regulation and DNA damage response, by combining biochemistry, X-ray crystallography and electron microscopy techniques. I will discuss our work on understanding the mechanisms of transcription regulation, especially how the initial DNA opening occurs during transcription initiation. I will also discuss our recent progress on elucidating structures and mechanisms of protein complexes involved in chromatin remodelling, DNA damage signalling and repair. 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)
Reference：
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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