Abstract P2-05-01: Chemotherapy-induced metastasis: Mechanisms and translational opportunities
Authors: Rivera Sanchez LG , Karagiannis GS , Wang Y , Sharma VP , Burt J , Entenberg D , Oktay M , Condeelis JS 
Published: May 2019

1 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, NY, USA

2 Integrated Imaging Program, Albert Einstein College of Medicine, NY, USA

3 Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, NY, USA

4 Department of Pathology, Albert Einstein College of Medicine, NY, USA

Background: Chemotherapy has become essential in the care of patients with advanced breast cancer. However, as we have previously discovered, chemotherapy may induce pro-metastatic changes in the breast cancer microenvironment by promoting the assembly and function of cancer cell intravasation sites called tumor microenvironment of metastasis (TMEM), and by increasing the proportion of the highly-invasive MenaINV-HI tumor cells that utilize TMEM sites for hematogenous dissemination. Consequently, chemotherapy-treated animals demonstrate increased numbers of circulating-tumor cells and micrometastases. Since the formation of metastases depends on both the presence of functional doorways for dissemination (TMEM) and cancer cells capable of using these doorways (MenaINV-HI tumor cells), we investigated the cellular and molecular contexts required for chemotherapy-mediated induction of TMEM function and MenaINV expression. Since TMEM function depends on Tie2 expressing macrophages and MenaINV expression is inducible by cancer cell -macrophage contact, we focused on inhibiting Tie2 receptors and chemotherapy-induced macrophage influx to inhibit chemotherapy-induced metastasis.

Materials and Methods: We used spontaneous models of mouse breast carcinoma (MMTV-PyMT) and patient-derived xenografts treated with chemotherapy with or without co-treatment with either Tie2 inhibitor (rebastinib), inhibitors of Cxcr4+ macrophage chemotaxis (Cxcl12 inhibitors) or macrophage depletion agents (clodronate). Pro-metastatic endpoints were measured by intravital imaging, multichannel immunofluorescence and standard metastasis dissemination assays.

Results: We demonstrated, using multiple methods of macrophage suppression, that chemotherapy-mediated induction of MenaINV-HI tumor cells depends on the presence of macrophages. In particular, depletion of either the entire macrophage lineage using clodronate liposomes or the use of specific inhibitors of the Cxcl12/Cxcr4 chemotactic pathway, resulted in a significant suppression of the MenaINV-hi cancer cell subpopulation in all mammary tumors examined. Moreover, inhibition of Tie2 by rebastinib blocked TMEM function and decreased the number of circulating tumor cells and metastatic foci, despite the chemotherapy-mediated induction of MenaINV-HI tumor cells.

Conclusions: Our data indicate that both the MenaINV-HI disseminating cancer cell population and the TMEM doorways are necessary but not individually sufficient for metastasis. As such, suppression of either the MenaINV-HI population or TMEM function can suppress chemotherapy-induced metastasis, thus providing a target to improve clinical care and eliminate non-beneficial effects of chemotherapy.

Citation Format: Rivera Sanchez LG, Karagiannis GS, Wang Y, Sharma VP, Burt J, Entenberg D, Oktay M, Condeelis JS. Chemotherapy-induced metastasis: Mechanisms and translational opportunities [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-01.