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Background: Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known., Methods: We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts., Results: We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1- 13 C]pyruvate and [1- 13 C]lactate interconversion in vivo., Conclusion: Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues., (© 2022. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% of cases. Mutations are commonly found in the signaling regulating the PI3K/Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of PI3K/Akt are members of the forkhead box O family (FOXO). FOXOs were initially considered as tumor suppressors by inducing cell cycle arrest and apoptosis. However, there is increasing evidence showing that FOXOs, especially FOXO3, can support tumorigenesis., Methods: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form., Results: We found that FOXO3 protein is significantly overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 induced extensive hepatic damage and elevated gene expression of several HCC-associated factors. Furthermore, FOXO3 expression enhanced hepatotoxicin-induced tumorigenesis. Mechanistically, FOXO3 activation caused oxidative stress and DNA damage and triggered positive feedback-loop for Akt activation as well as mTORC2 activation. Interestingly, FOXO3 activated not only reactive oxygen species (ROS)-promoting pathways, but also ROS-eliminating systems, which can be associated with the activation of the pentose phosphate pathway., Conclusions: FOXO3 is a master regulator of ROS in a 'carrot and stick' manner; on one side avoiding cellular crisis while also supporting hepatocellular carcinogenesis. Clinically, we suggest analyzing FOXO3 activation status in patients with liver diseases, in addition to PI3K/Akt signaling. Personalized therapy of FOXO3 inhibition may be a reasonable, depending on the activation status of FOXO3.

Background: Multimodal treatment with neoadjuvant chemoradiation followed by surgery (nCRT + S) is the treatment of choice for patients with locally advanced or node-positive esophageal squamous cell carcinoma (E-SCC). Those who are unsuitable or who decline surgery can be treated with definitive chemoradiation (dCRT). This study compares the oncologic outcome of nCRT + S and dCRT in E-SCC patients., Methods: Between 2011 and 2017, 95 patients with E-SCC were scheduled for dCRT or nCRT+ S with IMRT at our department. Patients undergoing dCRT received at least 50 Gy and those undergoing nCRT + S received at least 41.4 Gy. All patients received simultaneous chemotherapy with either carboplatin and paclitaxel or cisplatin and 5-fluoruracil. We retrospectively compared baseline characteristics and oncologic outcome including overall survival (OS), progression-free survival (PFS) and site of failure between both treatment groups., Results: Patients undergoing dCRT were less likely to have clinically suspected lymph node metastases (85% vs. 100%, p = 0.019) than patients undergoing nCRT + S and had more proximally located tumors (median distance from dental arch to cranial tumor border 20 cm vs. 26 cm, p < 0.001). After a median follow up of 25.6 months for surviving patients, no significant differences for OS and PFS were noticed comparing nCRT + S and dCRT. However, the rate of local tumor recurrence was significantly higher in patients treated with dCRT than in those treated with nCRT + S (38% vs. 10%, p = 0.002). Within a multivariate Cox regression model, age, tumor location, and tumor grading were the only independent parameters affecting OS and PFS. In addition to that, proximal tumor location was the only parameter independently associated with an increased risk for local treatment failure., Conclusion: In E-SCC patients treated with either dCRT or nCRT + S, a higher rate of local tumor recurrence was seen in patients treated with dCRT than in patients treated with nCRT + S. There was at least a trend towards an improved OS and PFS in patients undergoing nCRT + S. However, this should be interpreted with caution, because proximal tumor location was the only parameter independently affecting the risk of local tumor recurrence.

Background: Pancreatic ductal adenocarcinoma (PDAC) patients frequently present with borderline resectable disease, which can be due to invasion of the portal/superior mesenteric vein (PV/SMV). Here, we analyzed this group of patients, with emphasis on short and long-term outcomes., Methods: 156 patients who underwent a resection for PDAC were included in the analysis and sub-stratified into a cohort of patients with PV/SMV resection (n = 54) versus those with standard surgeries (n = 102)., Results: While venous resections could be performed safely, there was a trend towards shorter median survival in the PV/SMV resection group (22.7 vs. 15.8 months, p = 0.157). These tumors were significantly larger (3.5 vs. 4.3 cm; p = 0.026) and margin-positivity was more frequent (30.4% vs. 44.4%, p = 0.046)., Conclusion: Venous resection was associated with a higher rate of margin positivity and a trend towards shorter survival. However, compared to non-surgical treatment, resection offers the best chance for long term survival.

Background: Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). One important feature underlying the pathophysiology of many types of CVD is microvascular dysfunction. Although components of MetS are themselves CVD risk factors, the risk is increased when the syndrome is considered as one entity. We aimed to characterize microvascular function and some of its influencing factors in the course of MetS development., Methods: Development of MetS in C57BL/6 mice on a high-fat diet (HFD, 51% of energy from fat) was studied. The initial phase of MetS (I-MetS) was defined as the first 2 weeks of HFD feeding, with the fully developed phase occurring after 8 weeks of HFD. We characterized these phases by assessing changes in adiposity, blood pressure, and microvascular function. All data are presented as mean ± standard error (SEM). Differences between cumulative dose-response curves of myograph experiments were calculated using non-linear regression analysis. In other experiments, comparisons between two groups were made with Student's t-test. Comparisons between more than two groups were made using one-way ANOVA with Tukey post-hoc test. A probability value <0.05 was considered statistically significant., Results: I-MetS mice presented with weight gain, blood pressure elevation, and microvascular dysfunction characterized by augmented vasoconstriction. This finding, contrary to those in mice with fully developed MetS, was not associated with endothelial dysfunction, insulin resistance, or systemic inflammation. In the initial phase, perivascular adipose tissue showed no sign of inflammation and had no influence on the pattern of vasoconstriction. These findings suggest that the onset of hypertension in MetS is strongly influenced by vascular smooth muscle cell dysfunction and independent of important factors known to influence microvascular function and consequently blood pressure levels., Conclusion: We identified in I-MetS the occurrence of isolated augmented vasoconstriction along with blood pressure elevation, but not the presence of classical MetS components known to influence microvascular function. These findings increase our understanding of the pathophysiology of CVD risk associated with MetS.