Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

Abstract

The lack of approved targeted therapies highlights the need for new treatments for triple-negative breast cancer (TNBC) patients. Interleukin-3 (IL-3) acts as an autocrine factor for tumor–endothelial cells (TEC), and exerts pro-angiogenic paracrine action via extracellular vesicles (EVs). IL-3Rα blockade on TEC changes TEC-EV (anti-IL-3R-EV) microRNA (miR) content and promotes the regression of established vessels. As TEC is the doorway for “drug” entry into tumors, we aimed to assess whether IL-3R blockade on TEC impacts tumor progression via its unique EV cargo. First, the expression of IL-3Rα was evaluated in 27 human TNBC samples. It was noticed that, besides TEC and inflammatory cells, tumor cells from 55.5% of the human TNBC samples expressed IL-3Rα. Using human TNBC cell lines for in vitro studies, we found that, unlike native TEC-EVs (nEVs), anti-IL-3R-EVs increase apoptosis and reduced cell viability and migration. In vivo, anti-IL-3R-EV treatment induced vessel regression in established tumors formed of MDA-MB-231 cells, decreased Vimentin, β-catenin, and TWIST1 expression, almost abolished liver and lung metastases from primary tumors, and reduced lung metastasis generated via the intravenous injection of MDA-MB-231 cells. nEVs depleted of miR-24-3p (antago-miR-24-3p-EVs) were effective as anti-IL-3R-EVs in downregulating TWIST1 and reducing metastatic lesions in vivo. Consistent with network analyses of miR-24-3p gene targeting, anti-IL-3R-EVs and antago-miR-24-3p-EVs upregulate SPRY2 in MDA-MB-231 cells. Finally, SPRY2 silencing prevented anti-IL-3R-EV and antago-miR-24-3p-EV-mediated apoptotic cues. Overall, these data provide the first evidence that IL-3Rα is highly expressed in TNBC cells, TEC, and inflammatory cells, and that IL-3Rα blockade on TEC impacts tumor progression.

Applications of Extracellular Vesicles in Triple-Negative Breast Cancer

“…Membrane-embedded molecules on EVs can be used directly or indirectly against a target cell. For example, Lopatina et al used EVs embedded with an antibody against IL-3 receptors whereupon delivery to the MDA-MB-231 TNBC cell line expressing IL-3 receptor directly reduced the cell viability and cell migration [ 152 ]. Comparatively, EVs’ ability to transfer their membrane-embedded molecules to the recipient cell membrane upon fusion can confer the recipient cells with transiently selective receptors or antibodies for targeted therapy [ 166 , 167 , 168 ].…”

Emerging Advances of Detection Strategies for Tumor-Derived Exosomes

“…It is reasonable to hypothesize that the biological occurrence of inhibitory exosomes may largely lead to the loss of cancer cell migration, which will provide a feasible strategy for eliminating exosomes secreted in the tumor area and inhibiting the occurrence, development, and metastasis of cancer cells. Lopatina et al [ 83 ] demonstrated how the IL-3Rα blockade on tumor-endothelial cells reprograms extracellular vesicles, which then acquire the ability to change the expression of Vimentin, β-catenin, and TWIST1, and reduce angiogenesis and the metastatic spread of primary tumors. By comparing the miRNA map of ovarian cancer with the tumor-derived exosomal map separated from the oophoroma patient, Taylor et al [ 84 ] demonstrated the association between miRNA and circulating tumor-derived exosomes, and the results implied that miRNA analysis of circulating tumor exosomes could be used as an alternative diagnostic biomarker for biopsy analysis, extending its usefulness to screening asymptomatic populations.…”

Wnt pathway modulators in cancer therapeutics: An update on completed and ongoing clinical trials

“…99,100 Furthermore, this pathway is known to cross-talk with other signaling pathways, noncoding RNAs, miRNAs and cytokines in both health and disease, especially cancer. [101][102][103][104][105] Also, depending on the cell type, Considering the heterogeneous nature of cancer and the multiple pathways involved in disease progression/metastasis, it would be beneficial to conduct additional trials using combination therapy of Wnt-targeted drugs. Also, we need to explore the noncanonical pathway further to gain a better understanding of drug development.…”