Cooperation of Striatin 3 and MAP4K4 promotes growth and tissue invasion

MAP4K4 is associated with increased motility and reduced proliferation in tumor cells, but the regulation of this dichotomous functionality remained elusive. We find that MAP4K4 interacts with striatin 3 and 4 (STRN3/4) and that STRN3 and MAP4K4 exert opposing functions in Hippo signaling and clonal growth. However, depletion of either STRN3 or MAP4K4 in medulloblastoma cells reduces invasion, and loss of both proteins abrogates tumor cell growth in the cerebellar tissue. Mechanistically, STRN3 couples MAP4K4 to the protein phosphatase 2A, which inactivates growth repressing activities of MAP4K4. In parallel, STRN3 enables growth factor-induced PKCθ activation and direct phosphorylation of VASPS157 by MAP4K4, which both are necessary for efficient cell invasion. VASPS157 directed activity of MAP4K4 and STRN3 requires the CNH domain of MAP4K4, which mediates its interaction with striatins. Thus, STRN3 is a master regulator of MAP4K4 function, and disruption of its cooperation with MAP4K4 reactivates Hippo signaling and represses tissue invasion in medulloblastoma

Author Correction: Cooperation of Striatin 3 and MAP4K4 promotes growth and tissue invasion

MAP4K4 is associated with increased motility and reduced proliferation in tumor cells, but the regulation of this dichotomous functionality remained elusive. We find that MAP4K4 interacts with striatin 3 and 4 (STRN3/4) and that STRN3 and MAP4K4 exert opposing functions in Hippo signaling and clonal growth. However, depletion of either STRN3 or MAP4K4 in medulloblastoma cells reduces invasion, and loss of both proteins abrogates tumor cell growth in the cerebellar tissue. Mechanistically, STRN3 couples MAP4K4 to the protein phosphatase 2A, which inactivates growth repressing activities of MAP4K4. In parallel, STRN3 enables growth factor-induced PKCθ activation and direct phosphorylation of VASPS157 by MAP4K4, which both are necessary for efficient cell invasion. VASPS157 directed activity of MAP4K4 and STRN3 requires the CNH domain of MAP4K4, which mediates its interaction with striatins. Thus, STRN3 is a master regulator of MAP4K4 function, and disruption of its cooperation with MAP4K4 reactivates Hippo signaling and represses tissue invasion in medulloblastoma

A psychoeducational intervention reduces the need for anesthesia during radiotherapy for young childhood cancer patients

<p>Abstract</p> <p>Background</p> <p>Radiotherapy (RT) has become an important treatment modality in pediatric oncology, but its delivery to young children with cancer is challenging and general anesthesia is often needed.</p> <p>Methods</p> <p>To evaluate whether a psychoeducational intervention might reduce the need for anesthesia, 223 consecutive pediatric cancer patients receiving 4141 RT fractions during 244 RT courses between February 1989 and January 2006 were studied. Whereas in 154 RT courses corresponding with 2580 RT fractions patients received no psychoeducational intervention (group A), 90 RT courses respectively 1561 RT fractions were accomplished by using psychoeducational intervention (group B). This tailored psychoeducational intervention in group B included a play program and interactive support by a trained nurse according to age to get familiar with staff, equipment and procedure of radiotherapy.</p> <p>Results</p> <p>Group A did not differ significantly from group B in age at RT, gender, diagnosis, localization of RT and positioning during RT. Whereas 33 (21.4%) patients in group A got anesthesia, only 8 (8.9%) patients in group B needed anesthesia. The median age of cooperating patients without anesthesia decreased from 3.2 to 2.7 years. In both uni- and multivariate analyses the psychoeducational intervention significantly and independently reduced the need for anesthesia.</p> <p>Conclusion</p> <p>We conclude that a specifically tailored psychoeducational intervention is able to reduce the need for anesthesia in children undergoing RT for cancer. This results in lower costs and increased cooperation during RT.</p

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies

No wrong decisions in an all-wrong situation. A qualitative study on the lived experiences of families of children with diffuse intrinsic pontine glioma.

BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a rare, but lethal pediatric brain tumor with a median survival of less than 1 year. Existing treatment may prolong life and control symptoms, but may cause toxicity and side effects. In order to improve child- and family-centered care, we aimed to better understand the treatment decision-making experiences of parents, as studies on this topic are currently lacking. PROCEDURE The data for this study came from 24 semistructured interviews with parents whose children were diagnosed with DIPG in two children's hospitals in Switzerland and died between 2000 and 2016. Analysis of the dataset was done using reflexive thematic analysis. RESULTS For most parents, the decision for or against treatment was relatively straightforward given the fatality of the tumor and the absence of treatment protocols. Most of them had no regrets about their decision for or against treatment. The most distressing factor for them was observing their child's gradual loss of independence and informing them about the inescapability of death. To counter this powerlessness, many parents opted for complementary or alternative medicine in order to "do something." Many parents reported psychological problems in the aftermath of their child's death and coping strategies between mothers and fathers often differed. CONCLUSION The challenges of DIPG are unique and explain why parental and shared decision-making is different in DIPG compared to other cancer diagnoses. Considering that treatment decisions shape parents' grief trajectory, clinicians should reassure parents by framing treatment decisions in terms of family's deeply held values and goals

Correction to: Central nervous system tumors in children under 5 years of age: a report on treatment burden, survival and long-term outcomes

PURPOSE: The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population. METHODS: Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019. RESULTS: Median age at diagnosis was 1.81 years [IQR, 0.98–3.17]. Median follow-up time of surviving patients was 8.39 years [range, 0.74–23.65]. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8–86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up. CONCLUSION: Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-022-03963-3

Central nervous system tumors in children under 5 years of age: a report on treatment burden, survival and long-term outcomes

PURPOSE The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population. METHODS Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019. RESULTS Median age at diagnosis was 1.81 years [IQR, 0.98-3.17]. Median follow-up time of surviving patients was 8.39 years [range, 0.74-23.65]. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8-86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up. CONCLUSION Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children

Spatial proteomics finds CD155 and Endophilin-A1 as mediators of growth and invasion in medulloblastoma

The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell-cell and cell-matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin-mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. The decreased surface expression of CD155 or of the fast-endophilin-mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. In this study, we tested the hypothesis that single nucleotide polymorphisms identified by genome-wide association studies on adult glioma are also associated with PBT ris