CCR7-Driven Metastatic Spread is Shaped by the Microenvironment of Luminal Breast Tumors - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Polina Weitzenfeld ¹ Olga Kossover ² Cindy Körner ³ Tsipi Meshel ¹ Stefan Wiemann ³ Dror Seliktar ² Daniel Legler ⁴ Adit Ben-Baruch ¹

¹Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University
²Faculty of Biomedical Engineering, Technion-Israel Institute of Technology
³Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ)
⁴Biotechnology Institute Thurgau, University of Konstanz

Metastatic spread is a complex process, regulated both by internal characteristics of breast tumor cells, and by external stimuli from the tumor microenvironment (TME) and the distant pre-metastatic niches. Chemokine gradients in remote organs dictate homing of tumor cells to these sites. The CCR7-CCL21 axis mediates lymph node (LN) infiltration, while the CXCR4-CXCL12 pair is involved in bone metastases. Patient data revealed that luminal-A breast tumors express lower levels of CCR7 and CXCR4 compared to more aggressive subtypes. As the TME and tumor-regulating mechanisms differ amongst disease subtypes, we sought to evaluate the regulation of CCR7- and CXCR4-mediated metastatic spread by the TME in luminal-A tumors.

Our previously published study showed that stimulating luminal-A tumor cells by factors typical of the luminal TME – inflammatory mediators, hormones and growth factors - induced high metastatic potential. In our current study, we over-expressed CCR7 or CXCR4 in luminal breast tumor cells, endowing the cells with potent migratory capabilities in response to the chemokines, CCL21 and CXCL12, respectively. However, stimulating the cells with the "TME stimulation" has shut-off CCL21- and CXCL12-induced migration and inhibited chemokine-induced PI3K and MAPK activation. Furthermore, the "TME stimulation" shifted the metastatic balance in vivo: while naive CCR7-over-expressing luminal-A cells infiltrated LN efficiently, mice inoculated with TME-stimulated cells exhibited lower LN involvement, while demonstrating increased incidence of metastases in remote organs. Accordingly, CCR7 was found to be a poor indicator of LN metastases in luminal-A breast cancer patients.

This study demonstrates that the TME of luminal-A breast tumors dominates the activities of chemokine receptors in regulating site-specific metastases, and shifts the metastatic balance from LN-infiltration to remote metastases and therefore to a more aggressive phenotype.