TY - JOUR
T1 - A functional genomic screen in vivo identifies CEACAM5 as a clinically relevant driver of breast cancer metastasis
AU - Powell, Emily
AU - Shao, Jiansu
AU - Picon, Hector M.
AU - Bristow, Christopher
AU - Ge, Zhongqi
AU - Peoples, Michael
AU - Robinson, Frederick
AU - Jeter-Jones, Sabrina L.
AU - Schlosberg, Christopher
AU - Grzeskowiak, Caitlin L.
AU - Yang, Fei
AU - Wu, Yun
AU - Wistuba, Ignacio
AU - Moulder, Stacy L.
AU - Symmans, William F.
AU - Scott, Kenneth L.
AU - Edwards, John R.
AU - Liang, Han
AU - Heffernan, Timothy P.
AU - Piwnica-Worms, Helen
N1 - Funding Information:
The authors are grateful to the patients who provided the tumor samples for generating PDX models. Trang Tieu assisted with cloning and library array for GOF screens. Aaron McCoy provided quality control measures on PDX tumor samples. Shirong Cai and Yizheng Tu established PDX models used in this study. Vandhana Ramamoorthy provided assistance with cloning for CEACAM5 expression and shRNA constructs. Amanda Rinkenbaugh assisted with figure graphics. Alessandro Carugo provided suggestions on study design. Sendurai A. Mani, Gloria Echeverria, Vidya Sinha, Amanda Rinkenbaugh, Kristina Stemler, Abena Redwood, and Marimar de la Cruz Bonilla are thanked for helpful suggestions and critical feedback on the manuscript. Funding sources include Department of Defense Breast Cancer Research Program Postdoctoral Fellowship W81XWH-11-1-0616 (to E.P.), The Cancer Prevention and Research Institute of Texas RP150148 (to H.P.W.) and RP160710 (to W.F.S.); and NIH/NCI U24CA209851 and R01CA175486 (to H.L.). The MDACC Flow Cytometry and Cellular Imaging Core Facility are funded by National Cancer Institute Cancer Center Support Grant P30CA16672. PDX models and derivatives were obtained from the Cazalot Breast Cancer Model Resource at The University of Texas MD Anderson Cancer Center. This resource was established, in part, through a generous gift from the Cazalot family as well as from funding from the MDACC Breast Cancer Moonshot.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056700778&partnerID=8YFLogxK
U2 - 10.1038/s41523-018-0062-x
DO - 10.1038/s41523-018-0062-x
M3 - Article
C2 - 29736411
AN - SCOPUS:85056700778
VL - 4
JO - npj Breast Cancer
JF - npj Breast Cancer
SN - 2374-4677
IS - 1
M1 - 9
ER -