Metastatic disease is the major cause of death from cancer. However, just as not all primary cancers are prone to metastasize, not all tumor cells found at secondary sites are life-threatening. Dissemination from a primary tumor site can occur relatively early in tumor development, and cells at secondary sites may have properties that range from indolence to aggressive malignancy. This proposal is designed to address the provocative question How do we determine the significance of finding cells from a primary tumor at another site and what methods can be developed to make this diagnosis clinically useful? successfully answering this question would be expected to identify new Achilles' heels for tumors which could be the basis for developing novel therapeutics. The rationale for the proposed research is based on our preliminary studies showing that human breast cancer xenografts disseminate cells around the body and that these cells have distinct profiles that differ from the parent tumor. Given our novel insights, we now propose to analyze primary tumors and disseminated cells from human xenograft models of breast cancer for biomarkers of dissemination and metastasis; determine the heterogeneity of the cells in these populations by characterizing gene expression in single cells using micro-fluidic single cell PCR analysis; determine whether the disseminated tumor cells have the ability to initiate tumors upon transplantation; analyze the characteristics of the microenvironment of the disseminated tumor cells in which they flourish or remain indolent; and validate the hits for dissemination and metastasis. These studies will open up further studies with transplant of single cells of specific phenotypes, to learn which changes are crucial for metastasis. Understanding the molecular mechanisms of this complex interplay between malignant cancer cells and their surrounding non-malignant stroma represents one of the major challenges in cancer research, which once understood, will foster a better understanding of which disseminated tumor cells are quiescent and which are likely to give rise to metastases aggressively. This understanding will form the basis for new biomarkers and pharmacological interventions.

Public Health Relevance

A cure for breast cancer, the most common cancer in women, will require an understanding the molecular mechanisms by which breast cancer cells metastasize to distant organs. To address this major challenge in cancer research, we will investigate the properties of the cells that are found in distant organs and figure out whether they will lie dormant or grow as metastases. Once understood, these insights will foster the development of novel approaches in breast cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZCA1)
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Woodhouse, Elizabeth
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University of California San Francisco
Anatomy/Cell Biology
Schools of Medicine
San Francisco
United States
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Devignes, Claire-Sophie; Aslan, Yetki; Brenot, Audrey et al. (2018) HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice. Proc Natl Acad Sci U S A 115:E992-E1001
Shahi, Payam; Wang, Chih-Yang; Lawson, Devon A et al. (2017) ZNF503/Zpo2 drives aggressive breast cancer progression by down-regulation of GATA3 expression. Proc Natl Acad Sci U S A 114:3169-3174
Wang, Chih-Yang; Shahi, Payam; Huang, John Ting Wei et al. (2017) Systematic analysis of the achaete-scute complex-like gene signature in clinical cancer patients. Mol Clin Oncol 6:7-18
Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y et al. (2016) PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 22:1321-1329
Allaoui, Roni; Bergenfelz, Caroline; Mohlin, Sofie et al. (2016) Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun 7:13050
Plaks, Vicki; Kong, Niwen; Werb, Zena (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16:225-38
Casbon, Amy-Jo; Reynaud, Damien; Park, Chanhyuk et al. (2015) Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 112:E566-75
Sun, Zhengda; Lawson, Devon A; Sinclair, Elizabeth et al. (2015) Endovascular biopsy: Strategy for analyzing gene expression profiles of individual endothelial cells obtained from human vessels(?). Biotechnol Rep (Amst) 7:157-165
Lawson, Devon A; Bhakta, Nirav R; Kessenbrock, Kai et al. (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526:131-5
Lawson, Devon A; Werb, Zena; Zong, Yang et al. (2015) The Cleared Mammary Fat Pad Transplantation Assay for Mammary Epithelial Organogenesis. Cold Spring Harb Protoc 2015:pdb.prot078071