Biology subjects

Eriksson, P.

Publications and source records attributed to Eriksson, P..

10 recordsLinked to original sources

bioRxiv2025

CD44v6 Drives Tumor Aggressiveness and Chemoresistance in Bladder Cancer

Bladder cancer is a fast-moving and recurrent malignancy where survival hinges on early detection and precise risk stratification. The search for robust biomarkers is urgent, and CD44v6 has emerged as a compelling candidate. In this study, we reveal that CD44v6 is not merely a marker but a driver of urothelial carcinoma aggressiveness. Through integrated clinical and functional analyses, we show that high CD44v6 expression is strongly associated with poor patient outcomes. Mechanistic investigations demonstrate that CD44v6 amplifies the proliferative, migratory, and invasive potential of bladder cancer cells, while conferring marked resistance to cisplatin. These findings position CD44v6 at the intersection of tumor progression and therapeutic failure, underscoring its value as both a prognostic biomarker and a promising therapeutic target. Targeting CD44v6 could pave the way for strategies that curb disease aggressiveness and overcome chemoresistance in bladder cancer.

cancer biology↗

bioRxiv2025

Biologically-informed machine learning identifies a new clinically-actionable bladder cancer subgroup characterised by NRF2 overactivity

Muscle-invasive bladder cancer is a diverse disease where subtyping is ambiguous. Gene expression profiling followed by unsupervised machine learning (ML) has broadened our understanding of tumour biology, but has failed to provide high-confidence clinically-actionable subgroups. To focus on tissue-specific urothelial biology, we generated co-expression networks from histologically normal bladder, including multiple differentiation states and prioritising transcription factors (TFs). This strategy revealed an emergent set of 98 TFs which we used to stratify The Cancer Genome Atlas bladder cancer cohort, revealing a subdivision of basal tumours characterised by the detoxification and glutaminolysis activity of NRF2, rendering them resistant to standard bladder cancer interventions. These 20 tumours (4.9%) expressed squamous markers, were highly aggressive (15% 2-year survival), and had signatures of active PI3K, MTOR and retinoic acid signalling. Intriguingly, only half of the subgroup had activating mutations in the NRF2/KEAP1 pathway, whilst half of putative driver NFE2L2 mutations were excluded. This highlighted the importance of expression-based classification, particularly as re-analysis of NFE2L2-mutated lung cancer trial data showed only mutations consistent with our classification strategy responded to NRF2 inhibition. Our approach provides the first direct evidence that unsupervised ML can be biologically-informative in identifying clinically-actionable subgroups.

cancer biology↗

bioRxiv2024

Evaluation of gene expression-based predictors of lymph node metastasis in bladder cancer

The presence of cancer in pelvic lymph nodes removed during radical surgery for muscle-invasive bladder cancer (MIBC) is a key determinant of patient outcome. It would be beneficial to predict node status preoperatively to individually tailor the use of neoadjuvant chemotherapy and extent of lymph node dissection. Several studies have published node status predictors based on RNA expression signatures in the primary tumor, but none have been successfully validated in subsequent reports. We use gene expression data and node status from the two largest available MIBC cohorts to evaluate 12 published node-predictive signatures. Additionally, we examine the extent of overlap between differentially expressed genes and signatures across the two datasets, and we train new prediction models which we evaluate in cross-validation and by application to the independent cohort. All published node status predictors performed either no better than chance or only slightly better than chance in two independent validation datasets (maximal AUC 0.59 and 0.65 and maximum balanced accuracy 0.54 and 0.57 in the two cohorts). Most differentially expressed genes and signatures were only identified in one dataset and only a few, such as upregulation of interferon-response in node negative cases, were enriched in the same direction in both datasets. Transcriptomic predictors trained in one dataset performed poorly when applied to the other independent dataset (AUC 0.60 and 0.62). In this systematic evaluation, neither the 12 published signatures nor our own models reached an adequate performance for clinical node status prediction in independent data. This indicates that the biological determinants of nodal spread are poorly captured by bulk tumor RNA expression profiles.

cancer biology↗

bioRxiv2023

A versatile and upgraded version of the LundTax classification algorithm applied to independent cohorts

Stratification of cancer into biologically and molecularly similar subgroups is a cornerstone of precision medicine and transcriptomic profiling has revealed that urothelial carcinoma (UC) is a heterogeneous disease with several distinct molecular subtypes. The Lund Taxonomy classification system for urothelial carcinoma aims to be applicable across the whole disease spectrum including both non-muscle invasive and invasive bladder cancer. For a classification system to be useful it is of critical importance that it can be applied robustly and reproducibly to new samples. Many transcriptomic methods used for subtype classification are affected by the choice of expression platform, data preprocessing, cohort composition, and tumor purity. The application of a subtype classification system across studies therefore comes with a degree of uncertainty regarding whether the predictions in a new cohort accurately recapitulate the originally intended stratification. Currently, only limited data has been published evaluating the transferability and applicability of existing stratification systems and their respective classification-algorithms to external datasets. In the present investigation we develop a single sample classifier based on in-house microarray and RNA-sequencing data intended to be broadly applicable across datasets, studies, and tumor stages. We evaluate the performance of the proposed method and the Lund Taxonomical classification across 10 published bladder cancer cohorts (n=2560 cases) by examining the expression of characteristic subtype associated gene signatures, and whether complementary data such as mutations, clinical outcomes, response, or variant histologies are captured by our classification. Effects of varying sample purity on the classification results were also evaluated by generating low-purity versions of samples in silico. We show that the classifier is robustly applicable across different gene expression profiling platforms and preprocessing methods, and less sensitive to variations in sample purity. The classifier is available as the LundTaxonomy2023Classifier R package on GitHub.

bioinformatics↗

bioRxiv2022

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

Apolipoprotein-B (APOB) containing lipoproteins are causative for atherosclerotic cardiovascular disease. Whether the vasculature is the initial responding site or if atherogenic-dyslipidemia effects other organs simultaneously is unknown. We set out to discover how the liver responds to a dyslipidemic insult through the creation of inducible mouse models based on human familial hypercholesterolemia mutations and in vivo tracing of APOB. An acute transition to atherogenic APOB-lipoprotein plasma levels resulted in rapid accumulation of triglycerides and cholesterol in the liver. Single cell RNA-seq and flow cytometry disclosed that multiple immune cells have the ability to engulf APOB-lipoproteins. However bulk RNA-seq of the liver revealed an inflammatory Kupffer cell-specific transcriptional program that could not be activated by a western diet alone. Depletion of Kupffer cells through clodronate liposomes or CD8 T cell targeting rapidly raised plasma lipoprotein levels, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting pro-atherosclerotic factors into plasma. Our results place Kupffer cells as a key gateway in organizing systemic responses at the initiation of atherosclerosis.

immunology↗

bioRxiv2021

The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms

Arterial endothelial cells (ECs) have the ability to respond to mechanical forces exerted by fluid shear stress. This response is of importance, as it is protective against vascular diseases such as atherosclerosis and aortic aneurysms. Mechanical forces are transmitted at the sites of adhesion to the basal membrane as well as cell-cell junctions where protein complexes connect to the cellular cytoskeleton to relay force into the cell. Here we present a novel protein complex that connects junctional VE-cadherin and radial actin filaments to the LINC complex in the nuclear membrane. We show that the scaffold protein AmotL2 is essential for the formation of radial actin filaments and the flow-induced alignment of aortic and arterial ECs. The deletion of endothelial AmotL2 alters nuclear shape as well as subcellular positioning. Molecular analysis shows that VE-cadherin is mechanically associated with the nuclear membrane via binding to AmotL2 and Actin. Furthermore, the deletion of AmotL2 in ECs provokes a pro-inflammatory response and abdominal aortic aneurysms (AAA) in the aorta of mice on a normal diet. Remarkably, transcriptome analysis of AAA samples from human patients revealed a negative correlation between AmotL2 expression and aneurysm diameters, as well as a positive correlation between AmotL2 and YAP expression. These findings provide a conceptual framework regarding how mechanotransduction in the junctions is coupled with vascular disease.

cell biology↗

bioRxiv2020

Revealing interspecies transmission barriers of avian influenza A viruses

Influenza A virus (IAV) pandemics result from interspecies transmission events within the avian reservoir and further to mammals including humans. Investigating molecular virus-host interactions dictating this process and the adaptations to the new hosts that follow is vital to understand zoonotic IAV spread. Receptor incompatibility has been suggested to limit zoonotic IAV transmission from the wild bird reservoir. Other barriers to interspecies transmission, particularly within the avian system, largely remain elusive. Through assessment of infection dynamics of mallard origin IAV in two different avian hosts, coupled with studies of receptor expression and host response we aimed to reveal the host-pathogen interactions in a cross-species transmission event. We found that shedding patterns and innate immune responses were highly dependent on viral genotypes, host species and inoculation routes, but less dependent on receptor expression. Further, in contrary to the prevailing dogma we demonstrate that birds can produce a wide range of different sialylated structures also found in mammals, e.g. extended N- and O-linked Neu5Ac2,6 terminated glycans. Overall, receptor incompatibility is not the sole transmission barrier for IAV between birds and to humans, but other host-pathogen factors deserve dedicated studies to achieve proper pandemic preparedness.

microbiology↗

bioRxiv2018

The consensus molecular classification of muscle-invasive bladder cancer

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.

cancer biology↗

bioRxiv2018

High-resolution regulatory maps connect cardiovascular risk variants to disease related pathways

Genetic variant landscape of cardiovascular disease (CVD) is dominated by non-coding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct gene both to gain insights into perturbed functions and better assess the risk of disease. In this study, we generated high-resolution genomic interaction maps (~750 bases) in aortic endothelial, smooth muscle and THP-1 macrophages using Hi-C coupled with sequence capture targeting 25,429 features including variants associated with CVD. We detected interactions for 761 CVD risk variants obtained by genome-wide association studies (GWAS) and identified novel as well as established functions associated with CVD. We were able to fine-map 331 GWAS variants using interaction networks, thereby identifying additional genes and functions. We also discovered a subset of risk variants interacting with multiple promoters and the expression levels of such genes were correlated. The presented resource enables functional studies of cardiovascular disease providing novel approaches for its diagnosis and treatment.

genomics↗

bioRxiv2017

Genome-wide analysis yields new loci associating with aortic valve stenosis

Aortic valve stenosis (AS) is the most common valvular heart disease, characterized by a thickened and calcified valve causing left ventricular outflow obstruction. Severe AS is a significant cause of morbidity and mortality, affecting approximately 5% of those over 70 years of age1,2,3. Little is known about the genetics of AS, although recently a variant at the LPA locus4 and a rare MYH6 missense variant were found to associate with AS5. We report a large genome-wide association study (GWAS) with a follow-up in up to 7,307 AS cases and 801,073 controls. We identified two new AS loci, on chromosome 1p21 near PALMD (rs7543130; OR=1.20, P=1.2x10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR=1.15, P=1.8x10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR=1.28, P=6.6x10-10) and aortic root diameter (P=1.30x10-8) and rs1830321 associates with BAV (OR=1.12, P=5.3x10-3 and coronary artery disease (CAD) (OR=1.05, P=9.3x10-5). These results indicate that AS is partly rooted in the same processes as cardiac development and atherosclerosis.

genetics↗