Inhibin is a heterodimeric TGFβ family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers; however, its tumor-specific functions remain unknown. Here, we demonstrate that the α subunit of inhibin (INHA), which is critical for the functionality of dimeric inhibin A/B, correlates with microvessel density in human ovarian tissues and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that inhibin-regulated angiogenesis is necessary for metastasis. Although inhibin had no direct impact on tumor cell signaling, both tumor cell-derived and recombinant inhibin elicit a strong paracrine response from endothelial cells by triggering SMAD1/5 activation and angiogenesis i and Inhibin-induced angiogenesis was abrogated via anti-inhibin α antibodies. The endothelial-specific TGFβ receptor complex comprising ALK1 and endoglin was a crucial mediator of inhibin signaling, offering a molecular mechanism for inhibin-mediated angiogenesis. These results are the first to define a role for inhibin in tumor metastasis and vascularization and offer an antibody-based approach for targeting inhibin therapeutically. Inhibin is a predictor of poor patient survival in multiple cancers and is a potential target for antiangiogenic therapies. .

CDK8 is a transcription-regulating kinase that controls TGF-β/BMP-responsive SMAD transcriptional activation and turnover through YAP1 recruitment. However, how the CDK8/YAP1 pathway influences SMAD1 response in cancer remains unclear. Here we report that SMAD1-driven epithelial-to-mesenchymal transition (EMT) is critically dependent on matrix rigidity and YAP1 in a wide spectrum of cancer models. We find that both genetic and pharmacological inhibition of CDK8 and its homologous twin kinase CDK19 leads to abrogation of BMP-induced EMT. Notably, selectively blocking CDK8/19 specifically abrogates tumor cell invasion, changes in EMT-associated transcription factors, E-cadherin expression and YAP nuclear localization both in vitro and in vivo in a murine syngeneic EMT model. Furthermore, RNA-seq meta-analysis reveals a direct correlation between CDK8 and EMT-associated transcription factors in patients. Our findings demonstrate that CDK8, an emerging therapeutic target, coordinates growth factor and mechanical cues during EMT and invasion.

There is increased recycling of soluble fibronectin from the cell surface for fibrillogenesis. This recycling is regulated by TGF-β in a transcription- and SMAD-independent manner via specific TβRII and integrin α5β1 interactions. The recycling of fibronectin is Rab11 dependent and is required for TGF-β–induced cell migration.

Aberrant cell signaling in response to secreted growth factors has been linked to the development of multiple diseases, including cancer. As such, understanding mechanisms that control growth factor availability and receptor-growth factor interaction is vital. Dually modified transmembrane proteoglycans (DMTPs), which are classified as cell surface macromolecules composed of a core protein decorated with covalently linked heparan sulfated (HS) and/or chondroitin sulfated (CS) glycosaminoglycan (GAG) chains, provide one type of regulatory mechanism. Specifically, DMTPs betaglycan and syndecan-1 (SDC1) play crucial roles in modulating key cell signaling pathways, such as Wnt, transforming growth factor-β and fibroblast growth factor signaling, to affect epithelial cell biology and cancer progression. This review outlines current and potential functions for betaglycan and SDC1, with an emphasis on comparing individual roles for HS and CS modified DMTPs. We highlight the mutual dependence of DMTPs' GAG chains and core proteins and provide comprehensive knowledge on how these DMTPs, through regulation of ligand availability and receptor internalization, control cell signaling pathways involved in development and disease.

Edited by Xiao-Fan WangHyperactive Wnt/␤-catenin signaling is linked to cancer progression and developmental abnormalities, making identification of mechanisms controlling Wnt/␤-catenin signaling vital. Transforming growth factor ␤ type III receptor (T␤RIII/betaglycan) is a transmembrane proteoglycan co-receptor that exists with or without heparan and/or chondroitin sulfate glycosaminoglycan (GAG) modifications in cells and has established roles in development and cancer. Our studies here demonstrate that T␤RIII, independent of its TGF␤ co-receptor function, regulates canonical Wnt3a signaling by controlling Wnt3a availability through its sulfated GAG chains. Our findings revealed, for the first time, opposing functions for the different GAG modifications on T␤RIII suggesting that Wnt interactions with the T␤RIII heparan sulfate chains result in inhibition of Wnt signaling, likely via Wnt sequestration, whereas the chondroitin sulfate GAG chains on T␤RIII promote Wnt3a signaling. These studies identify a novel, dual role for T␤RIII/betaglycan and define a key requirement for the balance between chondroitin sulfate and heparan sulfate chains in dictating ligand responses with implications for both development and cancer.Wnt glycoproteins regulate three distinct Wnt signaling pathways to mediate cell fate, proliferation, and apoptosis as well as cancer initiation and progression in multiple cancers, including ovarian (1-9). Activation of the canonical Wnt/␤-catenin pathway begins with the binding of Wnt to its cell surface receptors, Frizzled and LDL receptor-related proteins 5/6 (LRP5/6), 3 followed by phosphorylation of LRP5/6, recruitment of Dishevelled to the plasma membrane to interact with Frizzled, and stabilization of cytosolic ␤-catenin (10). Axin interaction with phosphorylated LRP5/6 and Dishevelled leads to inactivation of the ␤-catenin destruction complex, accumulation of ␤-catenin, and translocation to the nucleus to regulate Wnt target genes by binding to TCF/LEF transcription factors (10, 11). The Wnt signaling cascade is controlled in part by transmembrane proteoglycans, which interact with Wnt signaling components and can either stimulate or inhibit signaling activity. For instance, the HSPG glypican-3 and syndecan-1 stimulate canonical Wnt signaling (12, 13), whereas others, including glypican-1 and glypican-6, suppress Wnt signaling (13,14). Type III TGF-␤ receptor (T␤RIII)/betaglycan is a transmembrane proteoglycan with loss resulting in embryonic lethality in mice (15). Beyond its roles in regulating TGF-␤ signaling, T␤RIII also controls several other pathways to inhibit cell migration, invasion, cell growth, and angiogenesis in both in vitro and in vivo cancer models (16 -22) and regulating differentiation through FGF2 signaling (23). Mechanistically, T␤RIII regulates these pathways either by altering the actin cytoskeleton, via T␤RIII/␤-arrestin2 cytoplasmic interactions (24), or by GAG chain interactions with FGF2 (23). Overall, T␤RIII also acts as a tumor suppressor in prostate (19), lung...