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Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. Short stature homeobox 2 ( ) and septin 9 ( ) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category ( < 0.001). Initially increased methylation levels were associated with a higher risk of death [ : hazard ratio (HR) = 5.27, = 0.001; : HR = 2.32, = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival ( : HR = 2.78, = 0.022; : HR = 2.50, = 0.026), and correlation with tumor and nodal category ( <0.001) were successfully validated. Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.

Background The development of molecular targeted agents (MTAs) has changed the treatment strategy for hepatocellular carcinoma (HCC). However, currently, there are no established predictive biomarkers for the treatment efficacy of MTAs. Previously, we developed a novel liquid biopsy test for HCC screening using sensitive methylated DNA testing of septin 9 gene ( SEPT9 ). Here, we hypothesized that SEPT9 could be used as a biomarker for MTA treatment efficacy. Methods We enrolled 157 patients receiving sorafenib or lenvatinib as a first-line therapy and allocated 85 and 72 patients to the training and validation cohorts, respectively. For the methylation assay, DNA was treated with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR. Various clinical parameters were compared with clinical outcomes. Results The multivariate analysis revealed Eastern Cooperative Oncology Group performance status (≥ 1; p  = 0.048), alpha-fetoprotein (AFP) (≥ 400 ng/mL; p  < 0.001), and methylated-septin-9 (m- SEPT9 ) (≥ 205 copies/mL; p  = 0.018) as significant predictors of poor overall survival (OS) in the training cohort. m- SEPT 9 was identified as a predictor of poor OS in the validation cohort. We developed a predictive score, called the MTA score, consisting of these three significant OS parameters (two points were added for AFP and one point for each of the other predictors). Patients with MTA scores ≥ 2 showed a significantly poor prognosis compared to those with MTA scores ≤ 1 in both the training and validation cohorts. Conclusions m- SEPT9 could be a potential predictive biomarker for survival in patients with HCC treated with MTAs. Graphical abstract

Septins are GTP-binding and membrane-interacting proteins with a highly conserved domain structure involved in various cellular processes, including cytoskeleton organization, cytokinesis, and membrane dynamics. To date, 13 different septin genes have been identified in mammals ( to and ), which can be classified into four distinct subgroups based on the sequence homology of their domain structure (SEPT2, SEPT3, SEPT6, and SEPT7 subgroup). The family members of these subgroups have a strong affinity for other septins and form apolar tri-, hexa-, or octameric complexes consisting of multiple septin polypeptides. The first characterized core complex is the hetero-trimer SEPT2-6-7. Within these complexes single septins can be exchanged in a subgroup-specific manner. Hexamers contain SEPT2 and SEPT6 subgroup members and SEPT7 in two copies each whereas the octamers additionally comprise two SEPT9 subgroup septins. The various isoforms seem to determine the function and regulation of the septin complex. Septins self-assemble into higher-order structures, including filaments and rings in orders, which are typical for different cell types. Misregulation of septins leads to human diseases such as neurodegenerative and bleeding disorders. In non-dividing cells such as neuronal tissue and platelets septins have been associated with exocytosis. However, many mechanistic details and roles attributed to septins are poorly understood. We describe here some important mammalian septin interactions with a special focus on the clinically relevant septin interactions.

Cell-autonomous immunity represents evolutionarily conserved defense mechanisms present in both immune and non-immune cells. One of such mechanisms is mediated by cytoskeletal septins that entrap cytosolic bacterial pathogens within cage-like structures. To promote infection, Shigella flexneri delivers effector proteins directly into host cells via a type III secretion system. Here we demonstrate that OspC effectors enable Shigella flexneri to evade septin cage entrapment. Mechanistically, OspC catalyzes ADP-riboxanation of SEPT9 at Arg561, a site essential for stabilizing septin hetero-oligomers. Notably, Arg561 ADP-riboxanation impairs septin polymerization and hence assembly of higher-order structures, including filaments and cage-like structures. Furthermore, we provide evidence that OspC effectors act synergistically with OspG to antagonize septin cage entrapment via two distinct post-translational modifications, thereby facilitating cell-to-cell spread and intracellular replication. Overall, our work reveals the elegant strategies of bacterial pathogens to evade septin-mediated cell-autonomous immunity and offers avenues for therapeutic intervention. Septin cages entrap cytosolic pathogens to restrict infection. Here, authors show that Shigella effectors OspCs catalyze ADP-riboxanation of SEPT9 at a critical interface, destabilizing septin octamers to inhibit cage assembly and evade host cell-autonomous immunity.

Septins are cytoskeletal proteins that form filaments and higher-order structures, and remodel membranes in a variety of processes. Structural and cell biological studies provided atomic- and micro-scale details, but the understanding of septin assembly at the mesoscale is limited. Here, we used high-speed atomic force microscopy (HS-AFM) to analyze yeast septin assembly on yeast supported lipid bilayers (SLBs). We found the coexistence of three lipid phases in yeast membranes, where septin polymerized selectively on the liquid-disordered phase. Septin filaments adhered to membranes with a conserved face; and paired filaments, previously reported in less native environments, were not observed. Additionally, septin filaments exhibited lateral and longitudinal alignment. We used HS-AFM force-sweep experiments to disrupt septin structures and observe organizational recovery through self-templating. Finally, septin filaments stacked, where higher layer filament alignment was templated by the layer below. Thus, septins encode their 3D-structural organization, likely tunable by the membrane and bulk environment. The authors use high-speed AFM to study the interaction of yeast septin filaments with yeast lipid membranes, showing that septin is lipid phase selective and organizes into higher-order structures without the contribution of other cellular components.

To cause nee blast disease, the fungus Magnaporthe oryzae develops a pressurized dome-shaped cell called an appressorium, which physically ruptures the leaf cuticle to gain entry to plant tissue. Here, we report that a toroidal F-actin network assembles in the appressorium by means of four septin guanosine triphosphatases, which polymerize into a dynamic, hetero-oligomeric ring. Septins scaffold F-actin, via the ezrin-radixin-moesin protein Tea1, and phosphatidylinositide interactions at the appressorium plasma membrane. The septin ring assembles in a Cdc42-and Chm1-dependent manner and forms a diffusion barrier to localize the inverse-bin-amphiphysin-RVS-domain protein Rvs167 and the Wiskott-Aldrich syndrome protein Las17 at the point of penetration. Septins thereby provide the cortical rigidity and membrane curvature necessary for protrusion of a rigid penetration peg to breach the leaf surface.

Methylated Septin 9 (SEPT9) is a sensitive biomarker for colorectal cancer (CRC) from peripheral blood. However, its relationship to cancer localization, guaiac-based fecal occult blood test (gFOBT) and carcinoembryonic antigen (CEA) have not been described. Plasma samples were collected for SEPT9 analysis from patients with no evidence of disease (NED) (n=92) before colonoscopy and CRC (n=92) before surgical treatment. DNA was isolated and bisulfite-converted using Epi proColon kit 2.0. Qualitative determination was performed using Epi proColon 2.0 RT-PCR assay. Samples for gFOBT and CEA analysis were collected from NED (n=17 and 27, respectively) and CRC (n=22 and 27, respectively). SEPT9 test was positive in 15.2% (14/92) of NED and 95.6% (88/92) of CRC, including 100% (67/67) from stage II to stage IV CRC and 84% (21/25) of stage I CRC when a sample was called positive if 1 out of 3 PCR replicates was positive. In a second analysis (2 out of 3 PCR replicates) specificity improved to 99% (91/92) of NEDs, at a sensitivity of 79.3% (73/92) of SEPT9 positives in CRC. gFOBT was positive in 29.4% (5/17) of NED and 68.2% (15/22) of CRC and elevated CEA levels were detected in 14.8% (4/27) of NED and 51.8% (14/27) of CRC. Both SEPT9 (84.8%) and CEA (85.2%) showed higher specificity than gFOBT (70.6%). SEPT9 was positive in 96.4% (54/56) of left-sided colon cancer (LSCC) cases and 94.4% (34/36) of right-sided colon cancer (RSCC) cases. gFOBT was positive in 83.3% (10/12) of cases with LSCC and 50% (5/10) of cases with RSCC, elevated CEA was detected 60% (9/15) of LSCC and 41.7% (5/12) of RSCC. The high degree of sensitivity and specificity of SEPT9 in plasma makes it a better method to detect CRC than gFOBT and CEA, even for the more difficult to detect RSCC.

Background As screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting. Objective We prospectively assessed the accuracy of circulating methylated SEPT9 DNA (mSEPT9) for detecting CRC in a screening population. Design Asymptomatic individuals ≥50 years old scheduled for screening colonoscopy at 32 US and German clinics voluntarily gave blood plasma samples before colon preparation. Using a commercially available assay, three independent blinded laboratories assayed plasma DNA of all CRC cases and a stratified random sample of other subjects in duplicate real time PCRs. The primary outcomes measures were standardised for overall sensitivity and specificity estimates. Results 7941 men (45%) and women (55%), mean age 60 years, enrolled. Results from 53 CRC cases and from 1457 subjects without CRC yielded a standardised sensitivity of 48.2% (95% CI 32.4% to 63.6%; crude rate 50.9%); for CRC stages I–IV, values were 35.0%, 63.0%, 46.0% and 77.4%, respectively. Specificity was 91.5% (95% CI 89.7% to 93.1%; crude rate 91.4%). Sensitivity for advanced adenomas was low (11.2%). Conclusions Our study using the blood based mSEPT9 test showed that CRC signal in blood can be detected in asymptomatic average risk individuals undergoing screening. However, the utility of the test for population screening for CRC will require improved sensitivity for detection of early cancers and advanced adenomas. Clinical Trial Registration Number: NCT00855348

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins represent a group of relatively well-conserved GTP-binding proteins that constitute the fourth component of the cytoskeleton. Septin 9 (SEPT9) has been linked to a diverse spectrum of malignancies and appears to be the most notable septin member in that category. SEPT9 constitutes a biomarker of colorectal cancer (CRC) and has been positively correlated with a high clinical stage in breast cancer, cervical cancer, and head and neck squamous cell carcinoma. SEPT9_i1 represents the most extensively studied isoform of SEPT9, which substantially contributes to carcinogenesis, metastasis, and treatment resistance. Nevertheless, the mechanistic basis of SEPT9_i1 oncogenicity remains to be fully elucidated. In this review, we highlight SEPT9’s and SEPT9_i1’s structures and interactions with Hypoxia Inducible Factor α (HIF-1 α) and C-Jun N-Terminal Kinase (JNK), as well as discuss SEPT9_i1’s contribution to aneuploidy, cell invasiveness, and taxane resistance—key phenomena in the progression of malignancies. Finally, we emphasize forchlorfenuron and other septin inhibitors as potential chemotherapeutics and migrastatics.

Septins are cytoskeletal filaments that assemble at the inner face of the plasma membrane. They are localized at constriction sites and impact membrane remodeling. We report in vitro tools to examine how yeast septins behave on curved and deformable membranes. Septins reshape the membranes of Giant Unilamellar Vesicles with the formation of periodic spikes, while flattening smaller vesicles. We show that membrane deformations are associated to preferential arrangement of septin filaments on specific curvatures. When binding to bilayers supported on custom-designed periodic wavy patterns displaying positive and negative micrometric radii of curvatures, septin filaments remain straight and perpendicular to the curvature of the convex parts, while bending negatively to follow concave geometries. Based on these results, we propose a theoretical model that describes the deformations and micrometric curvature sensitivity observed in vitro. The model captures the reorganizations of septin filaments throughout cytokinesis in vivo, providing mechanistic insights into cell division. Septins are cytoskeletal filaments that localize at constriction sites and impact membrane remodeling. Here authors examine the curvature sensitivity of septins using bilayers on wavy patterns and derive a theoretical model that quantitatively describe the results.