Stroma in the tumor microenvironment plays a critical role in cancer progression, but how it promotes metastasis is poorly understood. Exosomes are small vesicles secreted by many cell types and enable a potent mode of intercellular communication. Here, we report that fibroblast-secreted exosomes promote breast cancer cell (BCC) protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. We show that exosome-stimulated BCC protrusions display mutually exclusive localization of the core PCP complexes, Fzd-Dvl and Vangl-Pk. In orthotopic mouse models of breast cancer, coinjection of BCCs with fibroblasts dramatically enhances metastasis that is dependent on PCP signaling in BCCs and the exosome component, Cd81 in fibroblasts. Moreover, we demonstrate that trafficking in BCCs promotes tethering of autocrine Wnt11 to fibroblast-derived exosomes. This work reveals an intercellular communication pathway whereby fibroblast exosomes mobilize autocrine Wnt-PCP signaling to drive BCC invasive behavior.

Versican/PG-M is an extracellular matrix proteoglycan, expression of which is elevated in a variety of human tumors. The significance of this change is unclear. Here we show that versican G3-containing fragments are present at high levels in human astrocytoma. Expression of a versican G3 construct in U87 astrocytoma cells enhances colony growth in soft agarose gel and tumor growth and blood vessel formation in nude mice. The G3-containing medium enhances endothelial cell adhesion, proliferation, and migration. G3-expressing cells and tumors formed by these cells express increased levels of fibronectin and vascular endothelial growth factor (VEGF). Furthermore, the G3 domain directly binds to fibronectin and forms a complex together with VEGF. In the presence of these three molecules, endothelial cell adhesion, proliferation, and migration were found to be significantly enhanced. Removal of the complex containing these molecules reverses these processes. Taken together, these findings implicate G3 as a modifier of tumor growth and angiogenesis and suggest a new avenue for development of anticancer and anti-angiogenic therapies based on targeting versican G3 fragments.

Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGF␤, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGF␤-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.epithelial-to-mesenchymal transition ͉ cell polarity ͉ metastasis ͉ tumor invasion ͉ epithelial plasticity M etastasis, the spread of cancer cells from the primary tumor site to distant organs, accounts for over 90% of deaths in breast cancer patients (1). Metastasis has been associated with epithelial-to-mesenchymal transition (EMT), which is a complex manifestation of epithelial plasticity, in which polarized epithelial cells embedded in organized, stratified, or single cell layers convert into single fibroblastoid cells capable of locomotion (2). Cellular changes necessary for EMT include both morphological changes, as well as alterations in gene expression. While the role of the gene expression program associated with EMT has been well-described (3), it is unclear how the morphological changes associated with EMT specifically contribute to cancer progression and metastasis in vivo. The Par6 polarity complex localizes to the tight junction (TJ) and is an important regulator of the morphological transitions associated with epithelial cell plasticity (4). The complex is comprised of three highly conserved proteins, including Par3, Par6, and aPKC. Par6 is a core component that was initially identified as one of the six Par (for ''partitioning''-defective) proteins essential for asymmetric cell division in the C. elegans zygote, and was subsequently found to be required for asymmetric division of neuroblasts and the differentiation of oocytes in Drosophila, as well as the establishment/maintenance of apical-basal polarity and polarized migration in both Drosophila and mammalian cells. Par6-dependent control of apical-basal polarity is mediated by its interaction with Par3 and aPKC, as well as the Crumbs complex (4). Par6 is regulated directly by TGF␤ (5) and ErbB-2 receptors (6) to control epithelial cell plasticity and misregulation in expression of polarity proteins, including Scribb...