Abstract B030: Neoadjuvant chemotherapy promotes macrophage-induced MenaINV-dependent pro-metastatic changes in breast tumors

Abstract

Abstract Neoadjuvant chemotherapy (NAC) is used for treatment of localized breast cancer to decrease tumor size and improve surgical outcome. However, our recent study has uncovered a previously unrecognized side effect of NAC, which involves the induction of pro-metastatic changes in the primary breast cancer microenvironment. In particular, NAC promotes the assembly of structures that serve as doorways for intravasation of tumor cells called tumor microenvironment of metastasis (TMEM), and increases the proportion of the highly invasive and migratory MenaINV-hi/Mena11alo (MenaCalc+) tumor cells, which utilize the TMEM sites for hematogenous dissemination (1). MenaINV expression in particular is associated with decreased sensitivity of cancer cells to receptor tyrosine-kinase (RTK) and tyrosine-kinase (TK) inhibitors and with dramatically increased TMEM-dependent intravasation. The mechanism behind these pro-metastatic changes was not known. Here we report that NAC induces increased levels of Tie2Hi macrophages in the tumors, resulting in increased contact between macrophages and tumor cells leading to MenaINV expression in the cancer cells, and MenaINV-dependent TMEM assembly and tumor cell intravasation. Furthermore, we demonstrate that the Tie2 switch control inhibitor rebastinib sufficiently suppresses Tie2 signaling in macrophages, thereby inhibiting increased levels of Tie2Hi macrophages in the tumor, resulting in decreased MenaINV expression in the cancer cells and decreased TMEM-associated tumor cell intravasation. Our work has uncovered a previously unrecognized mechanism behind pro-metastatic changes in response to cytotoxic chemotherapy, the markers that predict these changes (TMEM, MenaCalc and MenaINV), and shows that this mechanism could be addressed by combining chemotherapy with rebastinib. Reference: 1. Karagiannis GS, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med 2017;9:aeen0026. Citation Format: George S. Karagiannis, Ved P. Sharma, Sara Brizio, Joseph Burt, Yarong Wang, David Entenberg, Bryan Smith, Daniel Flynn, Maja H. Oktay, John Condeelis. Neoadjuvant chemotherapy promotes macrophage-induced MenaINV-dependent pro-metastatic changes in breast tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B030.