A functional genomic screen in vivo identifies CEACAM5 as a clinically relevant driver of breast cancer metastasis

Autor: Zhongqi Ge, Ignacio I. Wistuba, Emily Powell, Timothy P. Heffernan, William Fraser Symmans, Sabrina Jeter-Jones, Christopher E. Schlosberg, Stacy L. Moulder, Michael Peoples, John R. Edwards, Fei Yang, Christopher A. Bristow, Hector M. Picon, Jiansu Shao, Kenneth L. Scott, Helen Piwnica-Worms, Yun Wu, Han Liang, Caitlin L. Grzeskowiak, Frederick S. Robinson
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: npj Breast Cancer, Vol 4, Iss 1, Pp 1-12 (2018)
NPJ Breast Cancer
ISSN: 2374-4677
DOI: 10.1038/s41523-018-0062-x
Popis: Tumor cells disseminate early in tumor development making metastasis-prevention strategies difficult. Identifying proteins that promote the outgrowth of disseminated tumor cells may provide opportunities for novel therapeutic strategies. Despite multiple studies demonstrating that the mesenchymal-to-epithelial transition (MET) is critical for metastatic colonization, key regulators that initiate this transition remain unknown. We serially passaged lung metastases from a primary triple negative breast cancer xenograft to the mammary fat pads of recipient mice to enrich for gene expression changes that drive metastasis. An unbiased transcriptomic signature of potential metastatic drivers was generated, and a high throughput gain-of-function screen was performed in vivo to validate candidates. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a metastatic driver. CEACAM5 overproduction enriched for an epithelial gene expression pattern and facilitated tumor outgrowth at metastatic sites. Tissues from patients with metastatic breast cancer confirmed elevated levels of CEACAM5 in lung metastases relative to breast tumors, and an inverse correlation between CEACAM5 and the mesenchymal marker vimentin was demonstrated. Thus, CEACAM5 facilitates tumor outgrowth at metastatic sites by promoting MET, warranting its investigation as a therapeutic target and biomarker of aggressiveness in breast cancer.
Metastasis: Protein implicated in cancer spread to the lungs A screen for drivers of metastasis has revealed a key protein involved in the spread of breast cancer into lung tissues. A US research team led by Helen Piwnica-Worms from the University of Texas MD Anderson Cancer Center in Houston enriched cells for genes involved in metastasis by engrafting mice with breast tumor biopsies taken from women with metastatic triple negative breast cancer and then metastases of these mice to mammary fat pads of recipient mice. The researchers pinpointed the gene encoding CEACAM5—a protein known to play a role in cell invasion and spread—as a key promoter of the cellular transition associated with metastasis. Tissues samples from patients confirmed that CEACAM5 levels were elevated in metastatic lung tumors relative to primary breast tumors. The protein provides a potential therapeutic target for drug development and candidate biomarker for patient stratification.
Databáze: OpenAIRE
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