Edinburgh Cancer Research

Neutrophils are abundant innate immune cells with remarkable plasticity, capable of exerting both antitumour and protumour functions. Beyond their local roles in the tumour microenvironment, recent studies highlight tumour-induced granulopoiesis as a systemic process by which cancers rewire haematopoiesis to expand immature neutrophils with immunosuppressive and tumour-promoting activity. Sustained by tumour-derived cytokines, chemokines and alarmins, tumour-induced granulopoiesis activates developmental programmes such as STAT3-C/EBPβ and RORC1, driving persistent neutrophilia and systemic immune suppression. Here, we review neutrophil maturation and heterogeneity, their dual roles in tumour initiation and progression, and the emerging recognition of tumour-induced granulopoiesis as a critical axis of tumour-host interaction with clinical and therapeutic implications.

Genetic and environmental factors contribute to depression. Among the latter, early life adversity and immune dysregulation have been consistently linked with depression. Childhood maltreatment (CM) is believed to induce immune dysregulation later in life. However, it is not known how CM might interact with genetic immune factors to contribute to the occurrence of depression. We investigated how genetic variability in 2370 genes from 20 immune pathways associates with a broadly-defined lifetime depression phenotype at gene- and pathway-level, and how this variability interacts with CM. Depression analysis was carried out in 13,309 individuals (1867 cases) from Generation Scotland (GS). CM interaction analysis was carried out in a subset of 749 individuals (99 cases) from GS and an independent sample of 509 individuals (96 cases) from the German BiDirect (BD) Study for which both genetic and CM data was available. Interactions with different types of CM were tested using the subscales of the childhood trauma questionnaire (CTQ). These results were meta-analyzed to obtain general gene-CM interactions. We found association of the GHR gene (false discovery rate -FDR- = 0.03, z = 4.2) and Reactome "RUNX1-regulated transcription of genes involved in myeloid cell differentiation pathway" (FDR = 0.016, beta = 1.2) with depression in GS. After meta-analysis, 56 immune gene-CM interactions were associated with depression (FDR < 0.05) in both GS and BD. These exert functions in hematopoiesis, pathogen recognition and stress responses, among others. Network analysis suggested macrophages as main expressing cell types. Our results underscore the involvement of hematopoietic alterations and immune gene-CM interactions in the development of depression.

Healthcare across Europe was affected by COVID-19 pandemic lockdowns. How different national healthcare systems coped with this impact remains unclear. Healthcare in Switzerland differs significantly from that in Scotland, for example, in terms of centralization. The aim of this study was to assess the impact of the COVID-19 pandemic on the diagnosis and surgical treatment of colorectal cancer (CRC) in contrasting healthcare systems. This retrospective cohort study was conducted in south-east Scotland and in the extended north-west of Switzerland from January 1st, 2019 to February 28th, 2023. All patients diagnosed with CRC were included. The primary outcomes were the time from CRC diagnosis to treatment and the UICC stage at diagnosis, assessed prior to, during, and following the period of lockdown. The lockdown in Scotland lasted from March 2020 to October 2020 and in Switzerland from March 2020 to April 2020. A total of 6745 patients were included (4127 from Scotland and 2618 from Switzerland). Median time from diagnosis to treatment remained unaltered during the lockdown period in both countries. However, after the lockdown, the median time from diagnosis to treatment increased from 59 to 76days in Scotland. The median number of patients who were diagnosed per annual quarter declined from 177 (IQR: 171-190) to 152 (IQR: 150-154), and the median number of who received treatment from declined from 256 (IQR: 253-259) to 203 (IQR: 186-218) during lockdown in Scotland. In multivariable logistic regression, the odds of being diagnosed with UICC stage IV increased by 42% for patients diagnosed during lockdown (95%-CI: 12%-81%). In Switzerland, the time from diagnosis to treatment increased slightly after the pandemic. However, the other effects described above were not observed in Switzerland. This descriptive study demonstrated that the impact of the pandemic on colorectal cancer care was less pronounced in Switzerland, but considerable in Scotland. Because separate subgroup analyses were conducted, direct comparisons cannot be made between Scotland and Switzerland. This trial is registered on clinicaltrials.gov as part of the EvaCol study (NCT04550156).

Single-cell RNA-sequencing (scRNA-seq) has advanced our understanding of the heterogeneity of synovial fibroblasts and their roles in tissue repair and osteoarthritis. Here, we compared the fibroblast responses to different types and duration of joint injury in mice. Published scRNA-seq data of synovial fibroblasts from a model of joint surface injury (JSI, day 6) and two post-traumatic osteoarthritis models, destabilisation of the medial meniscus (DMM, day 7 and 2 months) and anterior cruciate ligament rupture (ACLR, day 7 and day 28), were integrated and analysed using clustering, DEG, gene-set enrichment, regulon, pseudotime trajectory and cell-cycle analyses. The response to JSI was comparatively dominated by lining progenitor and fibroblast-like synoviocyte (FLS) expansion, while DMM and ACLR induced transient expansion of perturbed-state fibroblasts (PSF) containing a myofibroblast subset, followed by FLS expansion over time. Early injury responses were underpinned by proliferating cells that directly supplied new PSF and FLS. Molecular pathway analysis revealed rapid and sustained injury-induced transcriptomic shifts in both lining and sublining fibroblasts, with post-traumatic OA models in particular showing marked upregulation of matrix-related genes indicative of myofibroblast activity and tissue remodeling. Activity of regulons associated with the PSF response, including Hes6, Hif1α, Zfp354c, Runx1 and Foxp1, showed model and stage-dependent upregulation. Finally, co-expression of lineage-specifying transcription factors Sox9, Runx2 and Scx, indicative of multilineage potential, was a common feature of PSF in all injury models. This study uncovers similarities and differences in synovial fibroblast responses between injury models, guiding future research on joint repair and osteoarthritis.

BackgroundPrevious research has indicated an association between hypermobility and autism. This study examined whether being autistic affects diagnosis, symptoms, and health experiences of people with hypermobility, including hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). We compare three groups: autistic adults, non-autistic adults, and adults who are not autistic but have a high level of autistic traits. Additionally, we examined which health and social factors predicted self-reported physical and mental health outcomes for autistic and non-autistic people with hEDS/HSD.MethodA total of 1754 participants completed an online questionnaire about their diagnostic experience, hypermobile symptoms, co-occurring health conditions, self-rated physical and mental health, engagement with health services, and employment and benefits status. Around 25% of respondents were autistic; a further 25% had high levels of autistic traits.ResultsAutistic participants had more symptoms of hEDS/HSD and were more likely to have co-occurring physical and mental health conditions, compared with non-autistic and high autistic trait respondents. Autistic and high autistic trait participants self-reported poorer physical and mental health compared with non-autistic participants. Autistic participants’ mental health was impacted by limitations to everyday activities, whereas non-autistic participants were more impacted by difficulties with self-care.ConclusionsAutistic and non-autistic people may experience hEDS/HSD differently, which may impact the type of supports that are most beneficial to them.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-026-04713-2.

ABSTRACT Background Cystoscopy is a core component of haematuria investigations but is invasive and resource-intensive. GALEAS™ Bladder is a DNA-based diagnostic urine test that measures alterations in 23 bladder cancer-associated genes. Objective To assess the diagnostic performance and clinical utility of GALEAS™ Bladder as a molecular triage tool in real-world haematuria investigation pathways. Methods Patients referred for urgent investigation of haematuria were prospectively enrolled across seven UK NHS Urology Departments between October 2024 and June 2025. Urine samples were collected prior to cystoscopy and analysed using the GALEAS™ Bladder assay (Nonacus Clinical Services, UK). Assay results were compared with cystoscopy findings. Key Findings and Limitations Cystoscopic findings and GALEAS™ Bladder results were available for 964 participants, including 77 (8.0%) newly-diagnosed with pathology-confirmed BC. The assay demonstrated an overall sensitivity of 92.2% (95% CI: 84.0-96.4%), specificity of 92.0% (95% CI: 90.0-93.6%), and negative predictive value (NPV) of 99.3% (95% CI: 98.4-99.7%) for the diagnosis of BC. For the diagnosis of high-grade BCs, sensitivity was 97.2% (95% CI: 85.8-99.5%) with an NPV of 99.9% (95% CI:99.3-100.0%). Limitations include an absence of subsequent diagnoses for participants with positive GALEAS™ Bladder test results in the absence of cystoscopically-visible tumour. Conclusions and Clinical Implications GALEAS™ Bladder is a clinically implementable molecular urine test with very high sensitivity and specificity for the diagnosis of new cases of BC in patients undergoing urgent investigation of haematuria, especially for high-grade BCs. Clinical adoption could permit the molecular triage of haematuria patients to immediate or deferred cystoscopy.

Hydrophobic tagging (HyT) has emerged as a useful tool within the field of targeted protein degradation for the targeting and removal of a protein of interest (POI) from the cell. Development of new hydrophobic tags with increased efficiency not only allows increased POI degradation but also provides an opportunity to further study the mechanisms of HyT, which are not fully understood. Herein, we describe the development of new theranostic hydrophobic tags that can be used to induce protein degradation and simultaneously enable drug imaging using stimulated Raman scattering (SRS) microscopy. By coupling our dual-purpose theranostic hydrophobic tags to the PARP inhibiting, anti-cancer therapeutic olaparib, we explore the degradation efficiency, mode of action and potency that these theranostics confer in ovarian cancer cells. Lead compound 2c effectively degrades intracellular PARP-1 (DC50=0.618μM, Dmax=55%) and has more potent antiproliferative activity than the parent compound olaparib (IC50=62nM vs 11.52μM for olaparib), whilst maintaining on-target PARP inhibitory activity. Using mass spectrometry-based proteomic analysis, we demonstrate activation of the unfolded protein response, ER-stress and cell cycle arrest after incubation with 2c. Using SRS imaging, via the inherent Raman activity of the theranostic alkyne tag, we demonstrate involvement of the ER and autophagy after treatment with our drug conjugates. These results provide new insight into the mechanisms involved in HyT-induced protein degradation.

Despite widespread use of clinico-pathologic and genomic risk scores in early breast cancer (EBC), questions remain as to whether they are predictive, prognostic, or both. We evaluated risk score performance with actual patient outcomes in a trial dataset. Discrimination and calibration of PREDICT 2.1 and PREDICT v3 for overall survival (OS) and RSClin for distant metastasis-free survival (DMFS) were compared with actual patient outcomes in 645 postmenopausal, node-negative, hormone-positive patients with EBC from the TEAM pathology substudy. Estimated chemotherapy benefit (low < 3%, moderate 3-5%, high > 5%) was also compared. Harrell's C-statistic for OS was 0.6893 and 0.6986 for PREDICT 2.1 and v3, and 0.6603 for DMFS using RSClin. PREDICT 2.1 underestimated and PREDICT v3 overestimated the 10-year OS. RSClin underestimated the 10-year DMFS. Of patients predicted by RSClin to derive a large benefit from chemotherapy, 44% and 99% were estimated to have a small (< 3%) benefit by PREDICT 2.1 and v3, respectively. All three scores demonstrated moderate discriminatory ability while PREDICT v3 and RSClin had better calibration. However, scores varied widely on expected benefit from chemotherapy, suggesting that RSClin is prognostic but not predictive of chemotherapy benefit. Given the cost of RSClin, further studies are required. The trials are registered with ClinicalTrials.gov , NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial 27/2001; and UMIN, C000000057.

Background/Objectives: Cholangiocarcinoma (CCA) is a very aggressive biliary carcinoma characterised by significant molecular heterogeneity and restricted treatment alternatives. Despite genomic and proteomic investigations revealing recurrent changes, the signalling dynamics influencing tumour behaviour remain inadequately comprehended. Methods: We conducted high-resolution Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-based phosphoproteomics on paired tumour and surrounding tissues from 13 CCA patients in Northeast Thailand, meticulously sampling four geographically unique tumour areas for each patient. Our analysis concentrated on phosphoproteins consistently identified across all regions, delineating strong tumour-specific and cohort-wide phosphorylation signatures. Results: Notwithstanding considerable inter-patient variability, two conserved signalling modules were identified: an adhesion/Wnt axis regulated by hyperphosphorylated CTNNB1 protein (β-catenin) and a metal-handling module facilitated by metallothionein-1G (MT1G) protein and metallothionein-2A (MT2A) protein. Pathway enrichment identified focal adhesion, ECM-receptor interaction, cytoskeletal modulation, and mineral absorption as critical activities. Conclusions: This study elucidates conserved oncogenic pathways by analysing phosphoproteomic signatures across regional and patient-level variability, emphasising phosphoproteomics as a robust framework for biomarker and therapeutic development in CCA.