Purpose: Vimentin is an epithelial-to-mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis.Experimental Design: We used the LSL- CIPs correlate with tumor grade and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. A similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF motility to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion. Clin Cancer Res; 24(2); 420-32. Ó2017 AACR.

Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K-AKT-mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K-AKT-mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN-PI3K-AKT pathway in prostate cancer, with potential implications for combination targeted therapies against both primary and advanced prostate cancers.

Reference information: JCI Insight. 2017;2(5):e90487. https://

We investigated if previously demonstrated inhibition of fluciclovine (F) in vitro could be replicated in a PC3-Luc xenograft mouse model. Following intratumoral injection of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), alpha-(methylamino)isobutyric acid (MeAIB) or saline, fluciclovine PET tumor-to-background activity was 43.6 (± 5.4)% and 25.3 (± 5.2)% lower in BCH (n = 6) and MeAIB (n = 5) injected PC3 Luc xenografts, respectively, compared to saline-injected controls (n = 2). Partial inhibition of fluciclovine uptake by BCH and MeAIB can be demonstrated in vivo similar to previous in vitro modeling.

Prostate cancer is the most common cancer and the second leading cause of cancer mortality in American men, underscoring the significance of unraveling the molecular mechanisms involved in the initiation and progression of the disease. The sex-determining region Y-box 4 (SOX4) gene is overexpressed in many types of human cancers, including prostate cancer, suggesting that SOX4 plays a fundamental role in tumorigenesis. In this study, we demonstrate that SOX4 is critical for PTEN-mediated prostate cancer progression in vivo. We show that homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibits tumor progression initiated by homozygous loss of the Pten tumor suppressor, demonstrating the key role of SOX4 in the development of prostate cancer. Homozygous deletion of Sox4 also reduces the activation of AKT and β-catenin in Pten-null mice, resulting in inhibition of an invasive cancer phenotype. We also show that SOX4 expression is induced by loss of PTEN, and that PI3K-AKT-mTOR signaling activity is critical for SOX4 expression, suggesting a positive feedback loop between SOX4 protein and PI3K-AKT-mTOR activity. Our findings indicate that SOX4 is a critical component of the PTEN-PI3K-AKT pathway in prostate cancer, suggesting that SOX4 may be a promising molecular target for novel combinatorial therapies for both primary and advanced prostate cancers. Citation Format: Birdal Bilir, Adeboye O. Osunkoya, W. Guy Wiles, Soma Sannigrahi, Veronique Lefebvre, Daniel Metzger, Demetri D. Spyropoulos, W. David Martin, Carlos S. Moreno. SOX4 is essential for PTEN-mediated prostate tumorigenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2023.