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Sci Signal. 2017 Aug 8;10(491). pii: eaam8065. doi: 10.1126/scisignal.aam8065.

Breast tumors educate the proteome of stromal tissue in an individualized but coordinated manner.

Author information

1
Institute for Systems Genetics, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Medicine, Washington University in Saint Louis Medical School, St. Louis, MO 63110, USA.
4
Thermo Fisher Scientific, San Jose, CA 95134, USA.
5
Thermo Fisher Scientific, Rockford, IL 61101, USA.
6
Siteman Cancer Center, Washington University in Saint Louis Medical School, St. Louis, MO 63110, USA.
7
McDonnell Genome Institute, Washington University in Saint Louis Medical School, St. Louis, MO 63110, USA.
8
Lester and Sue Smith Breast Center, Department of Oncology, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
9
Institute for Systems Genetics, New York University School of Medicine, New York, NY 10016, USA. david@fenyolab.org jheld@wustl.edu.
10
Department of Medicine, Washington University in Saint Louis Medical School, St. Louis, MO 63110, USA. david@fenyolab.org jheld@wustl.edu.
11
Department of Anesthesiology, Washington University in Saint Louis Medical School, St. Louis, MO 63110, USA.

Abstract

Cancer forms specialized microenvironmental niches that promote local invasion and colonization. Engrafted patient-derived xenografts (PDXs) locally invade and colonize naïve stroma in mice while enabling unambiguous molecular discrimination of human proteins in the tumor from mouse proteins in the microenvironment. To characterize how patient breast tumors form a niche and educate naïve stroma, subcutaneous breast cancer PDXs were globally profiled by species-specific quantitative proteomics. Regulation of PDX stromal proteins by breast tumors was extensive, with 35% of the stromal proteome altered by tumors consistently across different animals and passages. Differentially regulated proteins in the stroma clustered into six signatures, which included both known and previously unappreciated contributors to tumor invasion and colonization. Stromal proteomes were coordinately regulated; however, the sets of proteins altered by each tumor were highly distinct. Integrated analysis of tumor and stromal proteins, a comparison made possible in these xenograft models, indicated that the known hallmarks of cancer contribute pleiotropically to establishing and maintaining the microenvironmental niche of the tumor. Education of the stroma by the tumor is therefore an intrinsic property of breast tumors that is highly individualized, yet proceeds by consistent, nonrandom, and defined tumor-promoting molecular alterations.

PMID:
28790197
PMCID:
PMC5712229
DOI:
10.1126/scisignal.aam8065
[Indexed for MEDLINE]
Free PMC Article

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