Biology subjects

Hofmann, W.-K.

Publications and source records attributed to Hofmann, W.-K..

5 recordsLinked to original sources

bioRxiv2026

scIRES-seq reveals multimodal molecular heterogeneity in CTCs from small cell cervical cancer

Circulating tumor cells (CTCs) can provide a window into cellular and molecular mechanisms of cancer dissemination. However, the rarity and heterogeneity of CTCs complicate reliable identification and molecular characterization. Here, we introduce scIRES-seq, a framework linking immunophenotype, genetic variation, epigenomic profiles and gene expression within individual cells. In this proof-of-concept study, we coupled scIRES-seq to real-time imaging spectral flow cytometry and applied it to CTCs from a patient with metastatic cervical small cell neuroendocrine carcinoma. Tumor-matched copy-number alterations and targeted somatic variants established CTC identity, supported by DNA methylation profiles concordant with metastatic tissue and transcriptional features consistent with neuroendocrine differentiation. Genetic and DNA methylation analyses identified two largely concordant CTC subpopulations that were not clearly distinguished by their transcriptomes, highlighting the complementary information gained through single-cell multi-omics profiling. These findings demonstrate the feasibility of integrated CTC identification and characterization and provide a framework for investigating relationships between genetic diversity and molecular states in rare, heterogeneous cell populations.

cancer biology↗

bioRxiv2025

Primary CD34+ cells of patients with VEXAS syndrome are highly sensitive to targeted treatment with TAK-243 and pevonedistat

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease characterized by somatically acquired UBA1 mutations in hematopoietic stem cells. VEXAS patients present with significant therapeutic challenges such as severe treatment-resistant inflammation and predisposition to myeloid malignancies. In this study, we evaluated the efficacy of TAK-243, a UBA1 inhibitor, and pevonedistat, a NEDD8 inhibitor, in vitro on primary CD34+ hematopoietic stem and progenitor cells (HSPCs) from patients with VEXAS syndrome (n=5), myelodysplastic neoplasms (MDS) (n=10), as well as healthy controls (n=10). Our findings revealed that VEXAS patient-derived HSPCs exhibited significantly higher sensitivity to both TAK-243 (IC50: 22 nM) and pevonedistat (IC50: 553 nM) compared to MDS (IC50: 133 nM and 1048 nM, respectively) and healthy controls (IC50: 192 nM and 1107 nM, respectively) as demonstrated by reduced cell viability. Furthermore, VEXAS CD34+ cells exhibited significantly higher levels of apoptosis after treatment with both inhibitors. These results suggest that TAK-243 and pevonedistat selectively target UBA1-mutated progenitor cells, and indicate a broad therapeutic window in which malignant cells are eradicated but healthy hematopoiesis is not yet compromised. This study provides a strong rationale for further clinical investigation of TAK-243 and pevonedistat as targeted therapies for VEXAS patients, offering hope for improved management of this clinically challenging disorder and contributing to our understanding of its underlying molecular mechanisms.

cancer biology↗

bioRxiv2021

Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states

Single-cell genomics has transformed our understanding of complex cellular systems. However, excessive costs and a lack of strategies for the purification of newly identified cell types impede their functional characterization and large-scale profiling. Here, we have generated high content single-cell proteo-genomic reference maps of human blood and bone marrow that quantitatively link the expression of up to 197 surface markers to cellular identities and biological processes across all major hematopoietic cell types in healthy aging and leukemia. These reference maps enable the automatic design of cost-effective high-throughput cytometry schemes that outperform state-of-the-art approaches, accurately reflect complex topologies of cellular systems, and permit the purification of precisely defined cell states. The systematic integration of cytometry and proteo-genomic data enables measuring the functional capacities of precisely mapped cell states at the single-cell level. Our study serves as an accessible resource and paves the way for a data-driven era in cytometry.

immunology↗

bioRxiv2020

Irradiated mesenchymal stromal cells induce genetic instability in human CD34+ cells

Radiation-induced bystander effects (RIBE) in human hematopoietic stem and progenitor cells may initiate myeloid neoplasms (MN). Here, the occurrence of RIBE caused by genotoxic signaling from irradiated human mesenchymal stromal cells (MSC) on human bone marrow CD34+ cells was investigated. For this purpose, healthy MSC were irradiated in order to generate conditioned medium containing potential genotoxic signaling factors. Afterwards, healthy CD34+ cells from the same donors were grown in conditioned medium and RIBE were analyzed. Increased DNA damage and chromosomal instability were detected in CD34+ cells grown in MSC conditioned medium when compared to CD34+ cells grown in control medium. Furthermore, reactive oxygen species and distinct proteome alterations, e.g., heat-shock protein GRP78, that might be secreted into the extracellular medium, were identified as potential RIBE mediators. In summary, our data provide evidence that irradiated MSC induce genetic instability in human CD34+ cells potentially resulting in the initiation of MN. Furthermore, the identification of key bystander signals, such as GRP78, may lay the framework for the development of next-generation anti-leukemic drugs.

cancer biology↗

bioRxiv2018

MutaSeq reveals the transcriptomic consequences of clonal evolution in acute myeloid leukemia

Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with i the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.

genomics↗