Citations

Abstract Glioma stem cells (GSC) and epithelial–mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360–73. ©2017 AACR.

Delivery of biomolecules to the correct subcellular locales is critical for proper physiological function. To that end, we have previously determined that type I and II transforming growth factor beta (TGF-β) receptors (TβRI and TβRII, respectively) localize to the basolateral domain in polarized epithelia. While TβRII targeting was shown to be regulated by sequences between amino acids 529 and 538, the analogous region(s) within TβRI is unknown. To address that question, sequential cytoplasmic TβRI truncations and point mutations identified a targeting motif between residues 158 and 163 (VxxEED) required for basolateral TβRI expression. Further studies documented that receptor internalization, down-regulation, direct recycling, or Smad signaling were unaffected by motif mutations that caused TβRI mislocalization. However, inclusion of amino acids 148–217 containing the targeting motif was able to direct basolateral expression of the apically sorted nerve growth factor receptor (NGFR, p75; extracellular and transmembrane regions) in a dominant manner. Finally, coexpression of apically targeted type I and type II TGF-β receptors mediated Smad3 signaling from the apical membrane of polarized epithelial cells. These findings demonstrate that the absence of apical TGF-β signaling in normal epithelia is primarily a reflection of domain-specific receptor expression and not an inability to couple with the signaling machinery.

Abstract While growing evidence suggests that tumor microenvironment can modulate stemness and the mesenchymal phenotype, little is known about how these cell states are coordinately regulated. We report that S100A4 controls both stemness and mesenchymal transition in GBM cells. In a spontaneous mouse glioma model and in primary human GBM tumorspheres, S100A4 expression is enriched in tumor-initiating cells and is required for self-renewal and tumor growth in vivo. In addition, greater than 80 percent of S100A4+ cells are associated with the tumor vasculature, a known niche for glioma stem cells, and S100A4 promotes pro-angiogenic factor expression. Interestingly, acidosis induces expression of S100A4 and the EMT regulators SNAIL1/2 and acidosis-induced EMT regulator expression requires S100A4 function. Importantly, S100A4 functions as a molecular switch between the proneural and mesenchymal states in GBM as S100A4 knockdown results in down-regulation of the mesenchymal signature genes, including the “master transcriptional regulators of mesenchymal transition”, and concurrent up-regulation of proneural signature genes. Together, these results indicate that S100A4 sits in a critical node in the molecular network that controls both glioma stem cells and the mesenchymal phenotype. Citation Format: Kin-Hoe Chow, Hee Jung Park, Joshy George, Yuanxin Chen, Andrew Gallup, Wen Jiang, Betty Y. Kim, Kyuson Yun. Regulation of GBM stemness and mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4783. doi:10.1158/1538-7445.AM2017-4783

Abstract Pulmonary fibrosis is a significant complication in cancer patients treated with radiation or various chemotherapeutic agents. One such reagent, bleomycin, is used to treat a variety of cancers including, but not limited to, lymphoma, ovarian cancer, and melanoma. Its efficacy, however, is impacted by the incidence of significant pulmonary fibrosis, which often becomes dose limiting. In studies investigating the role(s) of metabolism in the profibrotic actions of transforming growth factor beta, we previously determined that increased fatty acid synthase (FASN) expression was observed in the fibrotic areas of lungs from idiopathic pulmonary fibrosis (IPF) patients compared to healthy controls. In that FASN levels are significantly increased in numerous human tumors including breast, prostate, colorectal, and ovarian, we wished to integrate these findings by examining whether inhibiting FASN activity could reduce pulmonary fibrosis. To that end, the cerulenin-derived FASN inhibitor C75 was tested in a murine treatment model of bleomycin-induced lung fibrosis. Following addition of C75, there was significant diminution in a number of profibrotic targets including collagen 1α1, fibronectin, connective tissue growth factor, and total lung collagen as assessed by hydroxyproline content. Not only was there a C75 dose-dependent decrease in the aforementioned targets, but lung function as assessed by peripheral blood oxygenation (on room air) was also stabilized/improved. Thus, FASN inhibition might reflect a possible target to maintain normal lung physiology in the context of cancer chemotherapy. This work was supported by Public Health Service grants GM-055816 and GM-054200 from the National Institutes of General Medical Sciences. Citation Format: Mi-Yeon Jung. Fatty acid synthase is a risk factor for bleomycin-induced lung fibrosis in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 346. doi:10.1158/1538-7445.AM2017-346

Objective: To evaluate the relationship between donor sex and hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation. Background: HCC shows a male predominance in incidence and recurrence after tumor resection due to sex differences in hepatic sex hormone receptors. There have been no studies evaluating the importance of donor sex on post-transplant HCC recurrence. Methods: Of 384 recipients of livers, from living donors, for HCC: 104/120 who received grafts from female donors were matched with 246/264 who received grafts from male donors using propensity score matching, with an unfixed matching ratio based on factors like tumor biology. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. Results: The median follow-up time was 39 months. Before matching, recurrence probability at 1/2/5 years after transplantation was 6.1/9.7/12.7% in recipients with female donors and 11.7/19.2/25.3% in recipients with male donors. Recurrence risk was significantly higher with male donors in univariable analysis (hazard ratio [HR] = 2.04 [1.15–3.60], P = 0.014) and multivariable analysis (HR=2.10 [1.20–3.67], P = 0.018). In the matched analysis, recurrence risk was also higher with male donors (HR=1.92 [1.05–3.52], P = 0.034): both in intrahepatic recurrence (HR=1.92 [1.05–3.51], P = 0.034) and extrahepatic recurrence (HR=1.93 [1.05–3.52], P = 0.033). Multivariable analysis confirmed the significance of donor sex (HR=2.08 [1.11–3.91], P = 0.023). Interestingly, the significance was lost when donor age was >40 years. Two external cohorts validated the significance of donor sex. Conclusions: Donor sex appears to be an important graft factor modulating HCC recurrence after living donor liver transplantation.

AbstractIntroductionRapid eye movement sleep behavior disorder (RBD) is strongly associated with synucleinopathies. In 2012, we reported an increased risk of mild cognitive impairment (MCI) and Parkinson disease (PD) in cognitively normal Olmsted County, Minnesota, residents, aged 70 to 89 years with probable RBD. Here, we examine their progression to dementia and other neurodegenerative phenotypes.MethodsFifteen participants with RBD who were diagnosed with either MCI or PD were longitudinally followed, and their subsequent clinical courses were reviewed.ResultsOver 6.4 ± 2.9 years, six of the 14 participants with MCI developed additional neurodegenerative signs, five of whom had Lewy body disease features. Four of them progressed to dementia at a mean age 84.8 ± 4.9 years, three of whom met the criteria for probable dementia with Lewy bodies. One subject with PD developed MCI, but not dementia.DiscussionOur findings from the population‐based sample of Olmsted County, Minnesota, residents suggest that a substantial number of RBD patients tend to develop overt synucleinopathy features over time, and RBD patients who develop MCI and subsequent dementia have clinical features most consistent with dementia with Lewy bodies.

Objectives Congenital absence of the pericardium (CAP) is often confused with other conditions presenting with right ventricular dilatation and usually warrants CT or cardiac MR (CMR) to confirm. It would be desirable to have more specific echocardiographic criteria to provide a conclusive diagnosis. Methods 11 patients who were diagnosed with CAP (four patients with total CAP) based on CT/CMR were consecutively enrolled. Thirteen patients with atrial septal defect (ASD) and 16 normal subjects served as controls. To investigate spatial changes of heart in the thoracic cavity in CAP, following echocardiographic measurements were made in the left and right decubitus positions: the angle between the ultrasound beam and the left ventricular posterior wall (Angle-PW) in end-diastole at the parasternal long axis, and the distance between the chest wall and the most distal part of the left ventricular posterior wall (Distance-PW) at the parasternal mid-ventricular short axis. Results Angle-PW in patients with CAP were significantly greater than in those with ASD (100.1±12.5° vs 74.5±8.6°, p<0.017) or in normal subjects (100.1±12.5° vs 69.9±7.6°, p<0.017) at the left decubitus, and the difference in Angle-PW according to posture (left vs right) was significantly greater in CAP compared with the other groups (CAP 20.7±12.7°, ASD 0.31±1.80°, normal 0.31±1.40°, all p<0.017). The differences in Distance-PW according to patient position (CAP 2.43±0.77°, ASD 0.42±0.45°, normal 0.26±0.55°) or cardiac cycle in each position (left: CAP 1.60±0.76°, ASD 0.41±0.27°, normal 0.17±0.12°; right: CAP 0.70±0.32°, ASD 0.22±0.19°, normal 0.22±0.13°) were significantly higher in the CAP group than in the other groups (all p<0.017). Conclusions Patients with CAP have dynamic alteration in cardiac position depending on posture, which is not observed in ASD or in normal controls. Hence, total or left-sided CAP can be reliably diagnosed with positional changes during routine echocardiography.