Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. ß-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

Apert syndrome: an informative long-term dentofacial outcome.

The management of patients with Apert syndrome (AS) is complex and reflects the multisystem disease as a result of premature fusion of cranial vault, cranial base and midface sutures as well as extremity anomalies characterised by syndactyly. Early cranial sutural fusion results in craniocerebral disproportion which can lead to crisis surgical intervention due to raised intracranial pressure, ophthalmic and compromised airway concerns. Childhood inventions are often determined by psychosocial concerns and adult surgical interventions are often determined by cosmetic concerns. Treatments are provided by many different specialists within multidisciplinary teams (MDT). The treatment pathway extends from birth well into adulthood and is often associated with a heavy burden of care. Due to the extensive nature of the interaction with these patients MDT members have opportunities to provide enhanced patient-centred care and support.This case report provides an overview of the current knowledge of the aetiology of AS, illustrates the pathway of surgical and non-surgical management of AS and provides a long-term review of the dentofacial treatment outcomes.By having a better understanding of the impact of AS and treatment provided, MDT members can not only provide improved clinical treatment but also offer improved patient experiences for those with craniofacial anomalies, in particular, an increased awareness of the psychosocial challenges they endure.

Healthy Oral Lifestyle Behaviours Are Associated with Favourable Composition and Function of the Oral Microbiota.

Modifiable lifestyle interventions may influence dental disease by shifting the composition of the oral microbiota. This study aimed to test whether lifestyle traits are associated with oral microbiota composition and function. Swedish volunteers, aged 16 to 79 years, completed a lifestyle traits questionnaire including lifestyle characteristics and oral health behaviours. Bacterial 16S rDNA amplicons were sequenced and classified into genera and species, using salivary DNA. Microbiota functions were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and the KO Database of Molecular Functions by ortholog annotation. Tests for association used partial least squares and linear regression analysis with correction for multiple testing. The main analysis included 401 participants and 229 common bacterial species (found in ≥10% of the participants). The overall microbiota composition was strongly associated with questions "do you think caries is a disease?" and "do you use floss or a toothpick?". Enriched relative abundance of Actinomyces, Campylobacter, Dialister, Fusobacterium, Peptidophaga and Scardovia genera (all p < 0.05 after adjustment for multiple testing), and functional profiles showing enrichment of carbohydrate related functions, were found in participants who answered "no" to these questions. Socio-demographic traits and other oral hygiene behaviours were also associated. Healthier oral microbiota composition and predicted functions are found in those with favourable oral health behaviours. Modifiable risk factors could be prioritized for possible interventions.

Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells.

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.