The intestinal epithelium comprises a dynamic single cell layer in the gut that allows segregation of luminal content from the host while executing nutrient absorption, barrier maintenance, and ...danger signaling.Epithelial metabolism of nutrients allows for the maintenance of epithelial cell functions and host–microbe commensalism.Dietary cues, microbes and metabolites, immune cross-talk, endocrine signals, and neuronal networks control and regulate the execution of intestinal epithelial metabolism.Rewiring of epithelial metabolism constitutes a hallmark of inflammatory and malignant diseases in the gut.Extrinsic or intrinsic perturbation of intestinal epithelial metabolism promotes experimental gut inflammation and tumorigenesis.
The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host–microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future.
The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host–microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future.
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which ...cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with ...the selective FGFR1–4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low‐grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1‐ITD‐harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.
Ependymoma is a heterogeneous entity of central nervous system tumors with well-established molecular groups. Here, we apply single-cell RNA sequencing to analyze ependymomas across molecular groups ...and anatomic locations to investigate their intratumoral heterogeneity and developmental origins. Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations. The delineated transcriptomic signatures correlate with patient survival and define molecular dependencies for targeted treatment approaches. Taken together, our analyses reveal a developmental hierarchy underlying ependymomas relevant to biological and clinical behavior.
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•Cellular hierarchies in ependymoma reflect impaired neurodevelopment•Ependymoma cells follow neuronal-, astrocytic-, and ependymal-like trajectories•Undifferentiated programs confer inferior prognosis and are enriched at recurrence•Preclinical data suggest feasibility of inhibiting undifferentiated subpopulations
Gojo et al. use single-cell RNA sequencing to investigate intratumoral heterogeneity and cellular hierarchy in pediatric ependymoma, identifying impaired neurodevelopmental trajectories. The malignant trajectories reveal therapeutic targets and prognostic signatures in ependymoma.
Abstract
BRAFV600E mutations occur in 10-15% and homozygous CDKN2A deletions in approximately 40% of adolescent and pediatric high-grad glioma (HGG) and is associated with significantly decreased ...overall survival. Moreover, a subset of pHGG is defined by combined BRAFV600E mutation and concomitant CDKN2A homozygous deletion. Standard therapy has remained unchanged and consists of maximal safe resection and focal radiotherapy still resulting in poor overall survival. Therefore, new therapeutic approaches to increase patient survival are of utmost importance. Targeted therapy of BRAFV600E mutant HGG has emerged as effective treatment but remains challenging due to therapy resistance. CDK4/6 inhibitors represent a promising target in CDKN2A altered HGG. However, palbociclib demonstrated only low efficacy in HGG patients. Therefore, combination approaches may be more effective, and we investigated CDK4/6-inhibitors alone and in combination with trametinib in HGG cell models with BRAFV600E mutation and homozygous CDKN2A deletion.
Efficacy of CDK4/6-inhibitor monotherapy and combinatorial approach with trametinib was assessed by short- and long-term viability assays in four patient-derived HGG cell models with homozygous CDKN2A deletion and BRAFV600E mutation. Furthermore, effects of CDK4/6 inhibitor therapy alone or in combination with trametinib on downstream signaling pathways (MAPK, PI3K) were analyzed with Western blots.
Abemaciclib showed the highest activity in all cell models with IC50-values ranging from 0,5 – 2µM. Combined treatment approaches with trametinib showed synergistic effects across all cell models. Long-term viability assays revealed distinct sensitivity in the nanomolar range for CDK4/6-inhibitors and combined treatment with trametinib in all cell models. Exposure to abemaciclib and trametinib significantly decreased pRB, pERK, pS6, and pAKT protein expression levels when compared to monotherapy alone.
Summarizing, combined treatment with CDK4/6-inhibitors and trametinib showed promising therapeutic effects on HGG models with homozygous CDKN2A deletion and BRAFV600E mutation. Currently, effects on cell cycle distribution and downstream molecular mechanisms are investigated to identify potential predictive biomarkers.
Abstract
BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an ...Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (>1 and <2 years 0.25mg, >2 and <3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.
Abstract BACKGROUND Pediatric high-grade glioma (pHGG) is associated with poor overall survival and standard care has remained unchanged for the past decade. BRAFV600E mutations occur in 5-10% and ...dabrafenib in combination with mekinist is approved in this subtype. Nevertheless, acquired resistance to targeted therapeutics is a common setback in highly aggressive tumors. Homozygous CDKN2A/B loss co-occurs in approximately 60% of this pHGG subtype. Taking advantage of those combined molecular alterations and exploiting acquired resistance mechanisms is of utmost importance to increase overall survival in these patients. METHODS Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the effects of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combination treatment with trametinib on cell survival, cell cycle, apoptosis and senescence. RESULTS Abemaciclib showed the highest efficacy of CDK4/6 inhibitors comparable to trametinib monotherapy in our cell models. Abemaciclib led to a cell cycle arrest and combined treatment with trametinib induced distinctly increased levels of apoptosis in our tumor models when compared to monotherapy and a great proportion of surviving cells were senescent. One cell model was orthotopically implanted in mice and abemaciclib and combined treatment with trametinib showed a slightly increased response when compared to trametinib alone. CONCLUSIONS Summarizing, treatment with abemaciclib showed promising therapeutic effects in HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss comparable to trametinib alone. Levels of apoptosis were distinctly higher with combinatorial abemaciclib and trametinib treatment when compared to monotherapy alone and senescence was induced in a great number of surviving cells. In vivo abemaciclib was more efficient when compared to trametinib alone. Currently we are working on in vivo experiments and the effect on sustained induction of senescence and mechanisms of tumor cell growth after discontinuation of therapy and in a combinatorial metronomic approach and in combination with radiotherapy.
Background
Brain tumors are the most common solid malignancies and the leading cause of cancer‐related mortality in children. While numerous studies report on viral infections in children with ...hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking.
Objectives/study design
We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021. Demographic variables, quantitative and qualitative parameters of possible infections, and treatment outcomes were recorded.
Results
In our cohort (n = 117), 36% of the patients developed at least one PCR‐proven viral infection. Respiratory and gastrointestinal tract infections were most common, with 31% and 25%, respectively. Central nervous system (CNS) infections occurred in approximately 10%, with an almost equal distribution of varicella‐zoster virus, John Cunningham virus (JCV), and enterovirus. Two patients tested PCR‐positive for SARS‐CoV‐2 infection, with one virus‐related death caused by a SARS‐CoV‐2‐related acute respiratory distress syndrome. Patients receiving bevacizumab or mTOR inhibitors seem to have a greater susceptibility to viral infections.
Conclusion
Pediatric patients with brain tumors receiving targeted therapies have a higher risk of viral infections when compared to children receiving conventional chemotherapy or the general population, and life‐threatening infections can occur. Fast detection and upfront treatment are paramount to prevent life‐threatening infections in immunocompromised children suffering from brain tumors receiving targeted therapies.
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