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Background: Perineural invasion (PNI) frequently occurs in oral squamous cell carcinoma (OSCC) and predicts poor prognosis. Although PNI is increasingly recognised as a process driven by tumour-nerve crosstalk, the underlying molecular mechanisms remain unclear. We investigated the role of sympathetic nerve–derived neuropeptide Y (NPY) and its receptor NPY1R in OSCC PNI. Methods: NPY/NPY1R expression was assessed in human OSCC tissues by immunostaining, qPCR, and TCGA data analysis. Functional studies using Cal27 and SCC9 cells included migration, invasion, and sphere assays. The causal role of NPY1R was tested by lentiviral knockdown/overexpression, validated in tongue orthotopic xenografts, and further examined by NPY1R pharmacological inhibition in vivo. Results: NPY was enriched in the PNI microenvironment, and malignant OSCC expressed high NPY1R, particularly at invasive fronts. Mechanistically, NPY activated ERK and Smad2 via NPY1R, synergising with TGFβ signalling in tumour cells expressing TβRI. This crosstalk enhanced proliferation, invasion, and PNI in vivo. Importantly, NPY1R inhibition markedly reduced tumour growth, metastasis, and PNI. Conclusions: We identify NPY-NPY1R-TGFβ crosstalk as a novel mechanism enabling OSCC to exploit neural signals for PNI, highlighting a promising therapeutic target to block neural invasion and improve patient outcomes.

Background: Bladder cancer is one of the ten most common cancers worldwide. Its etiology is affected by several lifestyles, environment, and exposures such as smoking. Low vitamin D has been suggested as a risk factor. We aimed to evaluate vitamin D, D-vitamin binding protein (DVBP), and the free vitamin D index longitudinally in pre-diagnostic and diagnostic samples, as well as in patients with clinically diagnosed bladder cancer, in relation to control individuals.

Methods: The pre-diagnostic study population is derived from the population-based Northern Sweden Health and Disease Study (NSHDS). A total of 377 individuals were identified with the diagnosis of bladder carcinoma, and 377 matched controls from the same cohort. Furthermore, 353 patients were included, clinically diagnosed with bladder carcinoma, with blood samples from diagnosis. Of these, 129 had pre-diagnostic samples collected a median of 13.8 years earlier.

Results: Pre-diagnostic vitamin D, DVBP levels, and free vitamin D-index did not differ between those who later developed bladder cancer and controls. In the 129 patients with longitudinal samples, diagnostic Vitamin D levels were lower, and DVPB levels were higher at diagnosis compared to pre-diagnostic levels.

Conclusion: D-vitamin levels are lower at bladder cancer diagnosis compared to levels 13.8 years earlier. Additionally, the pre-diagnostic vitamin D levels did not differ from those of matched controls. Thus, we found no evidence that vitamin D would be an etiological risk factor for bladder cancer. The reduced D-vitamin levels at diagnosis in patients with bladder cancer instead indicate effects of the malignant disease itself.

Aims: To study the importance of decreasing tobacco smoking on the occurrence of larynx cancer in men and women.

Methods: The incidence rates of larynx cancer in the Swedish population between 1970 and 2021 were retrieved from the Swedish Cancer Register for ages 50–84 years, stratified for sex, age and calendar year. Data on the population’s smoking habits was retrieved from surveys and from taxation on the sale of cigarettes. The occurrence of larynx cancer was compared to smoking habits, sex and age. The time trends were compared between larynx and lung cancer.

Results: Over the years, Swedish men and women have had different smoking habits, especially older persons during the 1970s. In 1963, the prevalence of current smokers in women 50–69 years was 11%, while it was 46% in men. Around 2020, less than 10% of men and women in all age groups were current smokers. However, men had higher incidence rates of larynx cancer than women, even when their smoking habits were similar. For example, men and women 60–64 years of age in 2017–2021 had similar smoking habits during their life but the relative risk of larynx cancer in men compared to women was 3.3 (95% CI 1.7–4.8). However, pipe smoking was much more common in men.

Conclusions: The study indicates that other causes than cigarette smoking have an impact on the occurrence of larynx cancer in Sweden. Pipe smoking and occupational exposure to carcinogenic materials such as asbestos may be underlying causes of the difference in cancer risk between Swedish men and women.

TGFβ functions as a tumor suppressor or promoter, depending on the context, making TGFβ a useful predictive biomarker. Genes related to TGFβ signaling and Aurora kinase were tested for their ability to predict the progression risk of primary prostate tumors. Using data from The Cancer Genome Atlas (TCGA), we trained an elastic-net regularized Cox regression model including a minimal set of gene expression, copy number (CN), and clinical data. A multi-step feature selection and regularization scheme was applied to minimize the number of features while maintaining predictive power. An independent hold-out cohort was used to validate the model. Expanding from prostate cancer, predictive models were similarly trained on all other eligible cancer types in TCGA. AURKA, AURKB, and KIF23 were predictive biomarkers of prostate cancer progression, and upregulation of these genes was associated with promotion of cell-cycle progression. Extending the analysis to other TCGA cancer types revealed a trend of increased predictive performance on validation data when clinical features were complemented with molecular features, with notable variation between cancer types and clinical endpoints. Our findings suggest that TGFβ signaling genes, prostate cancer related genes and Aurora kinases are strong candidates for patient-specific clinical predictions and could help guide personalized therapeutic decisions.

Oral health in immature permanent teeth with traumatic injuries is particularly vulnerable, and regenerative endodontic treatment (RET) using stem cells from the apical papilla (SCAP) holds potential for root development and tissue regeneration. However, bacterial persistence, especially Enterococcus faecalis, poses a challenge to successful treatment outcomes. To address this, we evaluated the probiotic Lactobacillus gasseri for its co-aggregative and anti-adhesive properties against E. faecalis. An in vitro aggregation test demonstrated effective co-aggregation between the probiotic and opportunistic strains. Additionally, flow cytometry analysis revealed that E. faecalis binding to SCAP was significantly reduced when the L. gasseri concentration was nine times higher. To substantiate these findings, an in vivo Drosophila melanogaster gut model was used, where immunofluorescence imaging and culture-based methods confirmed decreased E. faecalis adhesion at both 1:1 and 9:1 probiotic-to-opportunistic ratios. These results highlight L. gasseri B16 as a promising probiotic strain to improve RET outcomes.

Protein kinases are key players in many eukaryotic signal transduction cascades and are as a result often linked to human disease. In humans, the mitotic protein kinase family of Aurora kinases consist of three members: Aurora A, B and C. All three members are involved in cell division with proposed implications in various human cancers. The human Aurora kinase B has in particular proven challenging to study with structural biology approaches, and this is mainly due to difficulties in producing the large quantities of active enzyme required for such studies. Here, we present a novel and E. coli-based production system that allows for production of milligram quantities of well-folded and active human Aurora B in complex with its binding partner INCENP. The complex is produced as a continuous polypeptide chain and the resulting fusion protein is cleaved with TEV protease to generate a stable and native heterodimer of the Aurora B:INCENP complex. The activity, stability and degree of phosphorylation of the protein complex was quantified by using a coupled ATPase assay, 31P NMR spectroscopy and mass spectrometry. The developed production system enables isotope labeling and we here report the first 1H–15N-HSQC of the human Aurora B:INCENP complex. Our developed production strategy paves the way for future structural and functional studies of Aurora B and can as such assist the development of novel anticancer drugs targeting this important mitotic protein kinase.

Background: The objective is to estimate the importance of the decrease of smoking habits in Sweden for the occurrence of lung cancer.

Methods: The change in smoking habits in the general population was retrieved from surveys and on taxation of sale of cigarettes. We used data from the Swedish Cancer Register on incidence of lung cancer between 1970 and 2021, stratified for sex, age and cell type, and compared the occurrence overtime in ages between 40 and 84 years.

Results: The sale of cigarettes peaked in 1980 to 1800 cigarettes per person and decreased to 600 per person in 2021. The change in incidence rates of squamous cell cancer and other cell types varied over time, sex, and age in a pattern that partly seems to be explained by change in the prevalence of daily smokers. The incidence of adenocarcinoma was similar in men and women 1970–2021 and increased, e.g. for women and men 75–79 years of age from around 20 cases in early 1970s to around 120 cases per 100 000 person-years in the 2020s.

Conclusions: Our data indicate that the risk of lung cancer several years after smoking cessation is less favourable than previously studies have indicated. There is a similar increase in the incidence of adenocarcinoma in men and women which is hard to explain only with changing smoking habits. The change from non-filter to filter cigarettes in the 1960s–1970s may be a contributing factor.

The crystal structure of the intracellular domain of transforming growth factor β type I receptor (TβR1) in complex with the competitive inhibitor SB505124 is presented. The study provides insights into the structure and function of TβR1 in complex with SB505124, and as such offers molecular-level understanding of the inhibition of this critical signalling pathway. The potential of SB505124 as an avenue for therapy in cancer treatment is discussed on basis of the results.

Adenoid cystic carcinoma (ACC) and basal cell adenoma (BCA) share many histological characteristics and often need a differential diagnosis in clinical pathology. Recently, we found homeobox protein engrailed-1 (EN1) was a potential diagnostic marker for ACC in an organoids library of salivary gland tumors (SGTs). Here we aim to confirm EN1 as a differential diagnostic marker for ACC, and further investigate the regulatory mechanism and biological function of EN1 in tumor progression. The transcriptional analysis, quantitative polymerase chain reaction, Western blot and immunohistochemistry staining were performed and revealed that EN1 was specifically and highly expressed in ACC, and accurately differentiated ACC from BCA. Furthermore, TGFβ signaling pathway was found associated with ACC, and the regulation of EN1 through TGFβ was detected in the human ACC cell lines and patient-derived organoids (PDOs). TGFβ-induced EN1 was important in promoting tumor budding in the PDOs model. Interestingly, a high level of EN1 and TGFβ1 in the budding tips was observed in ACC clinical samples, and the expression of EN1 and TGFβ1 in ACC was significantly associated with the clinical stage. In summary, our study verified EN1 is a good diagnostic marker to differentiate ACC from BCA. TGFβ-induced EN1 facilitates the tumor budding of ACC, which might be an important mechanism related to the malignant phenotype of ACC.