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Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery.

Abstract Background Although clinical data support an association between paternal alcohol use and deficits in child neurocognitive development, the relationship between paternal drinking and alcohol-induced growth phenotypes remains challenging to define. Using an established mouse model of chronic exposure, previous work by our group has linked preconception paternal alcohol use to sex-specific patterns of fetal growth restriction and placental dysfunction. The aim of the present study was to investigate the long-term impact of chronic preconception paternal alcohol use on offspring growth and metabolic programming. Results Preconception paternal alcohol exposure induced a prolonged period of fetal gestation and an increased incidence of intrauterine growth restriction, which affected the male offspring to a greater extent than the females. While the female offspring of ethanol-exposed males were able to match the body weights of the controls within the first 2 weeks of postnatal life, male offspring continued to display an 11% reduction in weight at 5 weeks of age and a 6% reduction at 8 weeks of age. The observed growth deficits associated with insulin hypersensitivity in the male offspring, while in contrast, females displayed a modest lag in their glucose tolerance test. These metabolic defects were associated with an up-regulation of genes within the pro-fibrotic TGF-β signaling pathway and increased levels of cellular hydroxyproline within the livers of the male offspring. We observed suppressed cytokine profiles within the liver and pancreas of both the male and female offspring, which correlated with the up-regulation of genes in the LiverX/RetinoidX/FarnesoidX receptor pathways. However, patterns of gene expression were highly variable between the offspring of alcohol-exposed sires. In the adult offspring of alcohol-exposed males, we did not observe any differences in the allelic expression of Igf2 or any other imprinted genes. Conclusions The impact of paternal alcohol use on child development is poorly explored and represents a significant gap in our understanding of the teratogenic effects of ethanol. Our studies implicate paternal exposure history as an additional and important modifier of alcohol-induced growth phenotypes and challenge the current maternal-centric exposure paradigm.