This study aimed to investigate the role of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) in glioblastoma (GBM) pathophysiology. To this end, PLOD2 protein expression was assessed by immunohistochemistry in two independent cohorts of patients with primary GBM (n₁ = 204 and n₂ = 203, respectively). Association with the outcome was tested by Kaplan–Meier, log-rank and multivariate Cox regression analysis in patients with confirmed IDH wild-type status. The biological effects and downstream mechanisms of PLOD2 were assessed in stable PLOD2 knock-down GBM cell lines. High levels of PLOD2 significantly associated with (p₁ = 0.020; p₂< 0.001; log-rank) and predicted (cohort 1: HR = 1.401, CI [95%] = 1.009–1.946, p₁ = 0.044; cohort 2: HR = 1.493; CI [95%] = 1.042–2.140, p₂ = 0.029; Cox regression) the poor overall survival of GBM patients. PLOD2 knock-down inhibited tumor proliferation, invasion and anchorage-independent growth. MT1-MMP, CD44, CD99, Catenin D1 and MMP2 were downstream of PLOD2 in GBM cells. GBM cells produced soluble factors via PLOD2, which subsequently induced neutrophils to acquire a pro-tumor phenotype characterized by prolonged survival and the release of MMP9. Importantly, GBM patients with synchronous high levels of PLOD2 and neutrophil infiltration had significantly worse overall survival (p < 0.001; log-rank) compared to the other groups of GBM patients. These findings indicate that PLOD2 promotes GBM progression and might be a useful therapeutic target in this type of cancer.

In the tumor host, neutrophils may exhibit protumor or antitumor activity. It is hypothesized that in response to host-derived or therapy-induced factors, neutrophils adopt diverse functional states to ultimately execute these differential functions. Here, we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions. Experimentally, we show that human neutrophils, which are sequentially stimulated with bacteria and secreted factors from tumor cells, kill a certain proportion of tumor target cells. However, the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional, phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition. This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model. Mechanistically, we identified the antimicrobial neutrophil granule proteins neutrophil elastase (NE) and matrix metalloprotease-9 (MMP-9) as the molecular mediators of this functional switch. We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9. Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis. The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.

Progesterone Receptor Membrane Component 1 (PGRMC1) is a tumour-promoting factor in several types of cancer but its role in brain tumours is poorly characterized thus far. Our study aimed to determine the effect of PGRMC1 on glioblastoma (GBM) pathophysiology using two independent cohorts of IDH wild-type GBM patients and stable knockdown GBM models. We found that high levels of PGRMC1 significantly predicted poor overall survival in both cohorts of GBM patients. PGRMC1 promoted the proliferation, anchorage-independent growth, and invasion of GBM cells. We identified Integrin beta-1 (ITGB1) and TCF 1/7 as potential members of the PGRMC1 pathway in vitro. The levels of ITGB1 and PGRMC1 also correlated in neoplastic tissues from GBM patients. High expression of PGRMC1 rendered GBM cells less susceptible to the standard GBM chemotherapeutic agent temozolomide but more susceptible to the ferroptosis inducer erastin. Finally, PGRMC1 enhanced Interleukin-8 production in GBM cells and promoted the recruitment of neutrophils. The expression of PGRMC1 significantly correlated with the numbers of tumour-infiltrating neutrophils also in tissues from GBM patients. In conclusion, PGRMC1 enhances tumour-related inflammation and promotes the progression of GBM. However, PGRMC1 might be a promising target for novel therapeutic strategies using ferroptosis inducers in this type of cancer.

The purpose of this study was to determine the role of Tctex1 (DYNLT1, dynein light chain-1) in the pathophysiology of glioblastoma (GBM). To this end, we performed immunohistochemical analyses on tissues from GBM patients (n = 202). Tctex1 was additionally overexpressed in two different GBM cell lines, which were then evaluated in regard to their proliferative and invasive properties. We found that Tctex1 levels were significantly higher in GBM compared to healthy adjacent brain tissues. Furthermore, high Tctex1 expression was significantly associated with the short overall- (p = 0.002, log-rank) and progression-free (p = 0.028, log-rank) survival of GBM patients and was an independent predictor of poor overall survival in multivariate Cox-regression models. In vitro, Tctex1 promoted the metabolic activity, anchorage-independent growth and proliferation of GBM cells. This phenomenon was previously shown to occur via the phosphorylation of retinoblastoma protein (phospho-RB). Here, we found a direct and significant correlation between the levels of Tctex1 and phospho-RB (Ser807/801) in tissues from GBM patients (p = 0.007, Rho = 0.284, Spearman’s rank). Finally, Tctex1 enhanced the invasiveness of GBM cells and the release of pro-invasive matrix metalloprotease 2 (MMP2). These findings indicate that Tctex1 promotes GBM progression and therefore might be a useful therapeutic target in this type of cancer.

Background: Aneurysmal subarachnoid hemorrhage (SAH) predominantly affects women, accounting for 65% of cases. Women have a 1.3 times higher relative risk than men, with the incidence rising particularly in women aged 55–85 years. Women also have a higher prevalence of unruptured intracranial aneurysms (IAs), especially after the age of 50 years, and are at greater risk of aneurysm growth and rupture. This study aimed to isolate the influence of sex on rupture rate, bleeding severity, functional outcomes, and complications by using a matched cohort, while also examining the impact of sex on aneurysm localization and multiplicity. Methods: We utilized a retrospectively collected database of 300 patients with 511 IAs. Inclusion criteria included the availability of clinical data and 3D angiography for semi-automatic reconstruction of IA morphology. Female patients and their IA were matched with male patients according to clinical parameters and 21 morphological characteristics using an interactive visual exploration tool for multidimensional matching. Results: Contrary to previously published results, our study found no significant sex differences in rupture rates or vasospasm rates between male and female patients. The severity of SAH, functional outcomes, and complications such as hydrocephalus were also similar in women and men. However, women exhibited a higher prevalence of multiple aneurysms and distinct localization patterns. Conclusions: This study underscores the complex role of sex in IA development and rupture. Although sex-specific biological factors influence aneurysm characteristics, they do not necessarily translate into differences in clinical outcomes. Further research is needed to explore these factors and their impact on aneurysm development and management.

Postoperative wound infections are a prevalent concern among the hospital-associated infections in Europe, leading to prolonged hospital stays, increased morbidity and mortality, and substantial patient burdens. Addressing the root causes of this complication is crucial, especially given the rising number of spine surgeries due to aging populations. Methods: A retrospective analysis was conducted on a cohort of 3019 patients who underwent lumbar spine surgery over a decade in our department. The study aimed to assess the predictors of wound healing disorders, focusing on laboratory values, particularly inflammatory parameters. Results: Of the 3019 patients, 2.5% (N = 74) experienced deep or superficial wound healing disorders, showing the significant correlation between C-reactive protein (CRP) levels and these disorders (p = 0.004). A multivariate analysis identified several factors, including age, sex, hypertension, diabetes, cardiac comorbidity, surgical duration, dural injury, and blood loss, as being correlated with wound healing disorders. Conclusion: Demographic factors, pre-existing conditions, and perioperative variables play a role in the occurrence of adverse effects related to wound healing disorders. Elevated CRP levels serve as an indicator of increased infection risk, though they are not a definitive diagnostic tool for wound healing disorders.