LAUSR

The progression of solid cancers towards a metastatic state is facilitated by tumor angiogenesis. While targeting of angiogenesis is an important therapeutic strategy, its success has been limited by an incomplete understanding of tumor endothelial cell (TEC) biology. Previous studies have demonstrated that miR-200, in addition to its wellestablished role in suppressing epithelial–mesenchymal transition (EMT), can inhibit tumor metastasis by regulating tumor angiogenesis. By analysing clinical information, Azam et al. [1] identify Quaking (QKI) as a key target of miR-200 supporting TEC function. Nanoparticle-mediated inhibition of QKI in TECs, or palbociclib blockade of cyclin D1 (a downstream target of QKI), were sufficient to perturb metastatic progression in a lung cancer model. This study highlights the therapeutic potential of targeting the miR-200-QKI axis to regulate tumor angiogenesis and limit metastasis. The tumour microenvironment (TME) is composed of a milieu of cell types, which interact and contribute to tumour progression. Tumour angiogenesis plays critical roles in both the growth of cancers and their metastasis. Accordingly, therapies aimed at inhibiting angiogenesis are an area of active development. In the case of anti-vascular endothelial growth factor (VEGF), responses in several cancers have displayed limited durability with frequent development of resistance mechanisms accompanying their use [2]. Here, Azam et al. [1] aimed to elucidate the function of miR-200 in tumour endothelial cells (TECs), following several studies showing this microRNA (miRNA) family plays important roles in endothelial cells (ECs) and angiogenesis [3–7]. The miR-200 family is a key regulator of epithelial–mesenchymal transition (EMT), a process that drives cancer cell invasion and metastasis in solid tumours [8, 9]. In this context, miR-200 strongly represses the EMT transcription factors ZEB1/2 in a double-negative feedback loop [10, 11], but also regulates a plethora of other genes including networks involved in the actin cytoskeleton [12, 13]. The authors have previously demonstrated that therapeutic administration of miR-200 to cancer cells reduced paracrine signalling, limiting tumour angiogenesis and metastasis [14], but its impact in TECs and the target genes it regulate remain unknown. Looking specifically at TECs compared with normal ECs in both a mouse model and human samples of lung adenocarcinoma, the authors found that miR-200b was reduced in the TECs of late-stage cancers. Probing as to the mechanisms through which miR-200b might regulate tumour angiogenesis, the authors combined clinical data from highly angiogenic and metastatic cancer types with genes specifically downregulated by transfection of miR200b into ECs. This led to the identification of the RNAbinding protein Quaking (QKI) as a lead candidate in modulating miR-200 function in TECs. Interestingly, similar data-mining approaches were recently used in two other reports in the context of EMT in cancer cells, also implicating QKI as a prominent miR-200 target gene in cancer progression [15, 16]. Together, these studies indicate that the miR-200-QKI axis may play potentially important roles across different cell types within the TME. To examine this more closely, the authors performed immunohistochemistry in cohorts of lung adenoand squamous cell carcinoma, partitioning tumours into endothelial (CD31-stained) and cancer cell (pan-cytokeratinstained) regions. Consistent with roles in tumour cell EMT [15, 17], QKI was expressed predominantly in leading-edge cancer cells near the vasculature but also widely throughout the tumour endothelium. In each compartment, the expression of QKI was associated with poor patient survival. These results pointed, for the first time, to an important function for QKI in TECs, and also suggested that QKI * Philip A. Gregory [email protected]