Research Papers:

Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

Larissa E. Hillebrand, Fee Bengsch, Jochen Hochrein, Jan Hülsdünker, Julia Bender, Marie Follo, Hauke Busch, Melanie Boerries and Thomas Reinheckel _

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Oncotarget. 2016; 7:58244-58260. https://doi.org/10.18632/oncotarget.11309

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Larissa E. Hillebrand1,2,3, Fee Bengsch1, Jochen Hochrein1,4,5, Jan Hülsdünker1, Julia Bender1, Marie Follo6, Hauke Busch1,4,5,7, Melanie Boerries1,4,5,7, Thomas Reinheckel1,3,5,7

1Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert-Ludwigs-University Freiburg, Freiburg, Germany

2Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany

3BIOSS Centre for Biological Signalling Studies, Freiburg, Germany

4Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany

5Comprehensive Cancer Center Freiburg, Freiburg, Germany

6Department of Hematology/Oncology, Core Facility, University Medical Center, Freiburg, Germany

7German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Thomas Reinheckel, email: [email protected]

Keywords: breast cancer, degradome, matrix metalloproteinase, proteolysis

Received: February 18, 2016     Accepted: July 27, 2016     Published: August 16, 2016


Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45, showed a high tumorigenicity compared to non-CD24+CD90+CD45 cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45 TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45 cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45- cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas.

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