Abstract 913: MENAINVexpression identifies a de novo chemotherapy-induced prometastatic subpopulation in breast cancer

Abstract Neoadjuvant chemotherapy (NAC) is used for treatment of localized breast cancer to decrease tumor size and improve surgical outcome. However, Karagiannis et al. (2017) has uncovered a previously unrecognized side-effect, which involves the induction of pro-metastatic changes in the primary breast cancer microenvironment, in response to NAC treatment. 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 (Karagiannis et al., 2017). 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 until recently. Here, we report that NAC induces an influx of macrophages in the tumors, resulting in increased contact between macrophages and tumor cells leading to MenaINV expression in the cancer cells, and MenaINV- and TMEM-dependent tumor cell intravasation. Multichannel IF imaging and distance analysis algorithms demonstrate that MENAINV-hi cells have a higher probability of being in direct cell contact with infiltrating macrophages in chemotherapy-treated tumors. Specific depletion of the macrophage lineage in transgenic MMTV-PyMT mice developing spontaneous breast carcinoma and patient-derived xenografts results in a significant suppression of the prometastatic MenaINV-hi cancer cell subpopulation. Moreover, chemotherapy-induced MenaINV expression in tumor cells is not seen in such macrophage-depleted mice, indicating that macrophage influx is both necessary and sufficient for the generation of the de novo prometastatic tumor cell subpopulation. These data provide an explanation as to why mice and patients with breast cancer do not always respond with a decrease in circulating tumor cells (CTCs), or even respond with a slight increase, following cytotoxic NAC treatment. Our work has uncovered a previously unrecognized mechanism behind pro-metastatic changes in response to cytotoxic chemotherapy and the markers that predict these changes (TMEM, MenaCalc and MenaINV). Reference: Karagiannis GS, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through aTMEM-mediated mechanism. Sci Transl Med, 2017; 9 aeen0026. Citation Format: George S. Karagiannis, Luis Rivera Sanchez, Yarong Wang, Ved P. Sharma, Joseph Burt, Sara Brizio, David Entenberg, Maja H. Oktay, John S. Condeelis. MENAINV expression identifies a de novo chemotherapy-induced prometastatic subpopulation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 913.