Abstract
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.
Highlights
Metastatic breast cancer is incurable in most cases.[1]
Serial passaging of lung metastases in vivo enriches for metastatic potential The patient-derived xenograft (PDX) line WU-BC3 was generated by engrafting breast tumor cells from a patient with metastatic Triple negative breast cancer (TNBC) into the humanized mammary fat pads (MFPs) of NOD/SCID mice mice.[26,27]
We demonstrated that tumor cells metastasized from MFPs to physiologically relevant sites including lung, liver, bone, brain, and lymph nodes.[28]
Summary
Metastatic breast cancer is incurable in most cases.[1]. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is characterized by high rates of metastasis and poor prognosis.[2,3]. TNBC preferentially metastasizes to visceral organs including lungs.[2]. Metastasis is a multistep process that includes escape from the primary tumor, survival in the blood circulation, extravasation, and tumor outgrowth in the metastatic site.[4]. Successful completion of each of these steps is essential for the formation of macroscopic metastatic disease. The development of novel strategies to prevent or treat metastatic TNBC will rely on defining properties of the tumor cell as well as the metastatic niche that enable dissemination, seeding, and outgrowth of metastatic tumor cells.[5,6]
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