Biology subjects

Pfarr, N.

Publications and source records attributed to Pfarr, N..

4 recordsLinked to original sources

bioRxiv2026

Alternative lengthening of telomeres stratifies complex karyotype sarcomas into distinct genomic and transcriptomic states

Complex karyotype sarcomas (CKS) are heterogeneous mesenchymal malignancies that typically lack recurrent actionable oncogenic drivers and remain therapeutically challenging. Loss of ATRX is a recurrent feature of CKS and defines a particularly high-risk subgroup. ATRX loss is also associated with activation of the alternative lengthening of telomeres (ALT) pathway, and ALT-positive sarcomas have been linked to poor clinical outcomes. However, the molecular underpinnings underlying ALT-status-dependent differences in CKS, as well as the therapeutic vulnerabilities associated with ALT, remain poorly defined. By integrating C-circle-based ALT detection across 776 sarcoma samples with multi-modal sequencing of five CKS subtypes, we find that ALT activity is associated with enriched hallmarks of genomic instability. ALT-positive transcriptomes are dominated by a coordinated DNA damage response and mitotic program, in contrast to oncogenic signaling pathways that drive TERT activation in ALT-negative tumors. Long-read sequencing reveals telomere repeat clusters and telomere-mediated healing at structural breakpoints in ALT-positive tumors. These events also occur on extrachromosomal DNA (ecDNA), linking ALT activity to ecDNA biology. Together, our findings position ALT status as an important stratifying feature of CKS and identify ALT-associated transcriptional programs as potential therapeutic targets.

cancer biology↗

bioRxiv2025

Multi-modal analysis of satellite cells reveals early impairments at pre-contractile stages of myogenesis in Duchenne muscular dystrophy

Recent studies on the role of myogenic satellite cells (SC) in Duchenne muscular dystrophy (DMD) documented altered division capacities and impaired regeneration potential of SC in DMD patients and animal models. It remains unknown, however, if SC-intrinsic effects trigger these deficiencies at pre-contractile stages of myogenesis rather than resulting from the pathologic environment. Addressing this, we isolated SC from muscle biopsies of a porcine DMD model for characterization. Traction force microscopy (TFM) revealed that DMD SC produce a significantly higher strain energy than wild-type cells (WT; 0.136 {+/-} 0.016 {micro}J vs. 0.057 {+/-} 0.008 {micro}J). By RNA-seq, we identified 1,390 differentially expressed genes and proteomics measurements detected 1,261 proteins with altered abundance in DMD vs. WT. Dysregulated pathways uncovered by Gene Ontology (GO) enrichment analysis included sarcomere organization, focal adhesion, and response to hypoxia. We integrated the data using multi-omics factor analysis (MOFA) and identified five factors accounting for the variance with an overall higher contribution of the transcriptomic (61.95 %) than the proteomic data (54.02 %). Our findings suggest SC impairments result from their inherent genetic abnormality rather than environmental influences. The observed biological changes are independent and not reactive to the pathological surrounding of DMD muscle.

pathology↗

bioRxiv2022

The Limits of Molecular Signatures for Pancreatic Ductal Adenocarcinoma Subtyping

Molecular signatures have been suggested as biomarkers to classify pancreatic ductal adenocarcinoma (PDAC) into two, three or four subtypes. Since the robustness of existing signatures is controversial, we performed a systematic evaluation of three established signatures for PDAC stratification across eight publicly available datasets. Clustering revealed inconsistency of subtypes across independent datasets and in some cases a different number of PDAC subgroups than in the original study, casting doubt on the actual number of existing subtypes. Next, we built nine classification models to investigate the ability of the signatures for tumor subtype prediction. The overall classification performance ranged from [~]35% to [~]90% accuracy, suggesting instability of the signatures. Notably, permuted subtypes and random gene sets achieved very similar performance. Cellular decomposition and functional pathway enrichment analysis revealed strong tissue-specificity of the predicted classes. Our study highlights severe limitations and inconsistencies that can be attributed to technical biases in sample preparation and tumor purity, suggesting that PDAC molecular signatures do not generalize across datasets. How stromal heterogeneity and immune compartment interplay in the diverging development of PDAC is still unclear. Therefore, a more mechanistic or at least multi-omic approach seems necessary to extract more robust and clinically exploitable insights.

bioinformatics↗

bioRxiv2020

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.

cancer biology↗