Biomedical subjects

Jens Luebeck

Publications and source records attributed to Jens Luebeck.

4 recordsLinked to original sources

PubMed2026

scAmp enables focal gene amplification analysis from single-cell data.

Oncogene amplification on extrachromosomal DNA is a common driver of tumor progression and is associated with acquired drug resistance and poor patient survival. While bulk whole genome sequencing studies have revealed the landscape of genes amplified on extrachromosomal DNA in tumors, it remains challenging to study the subclonal heterogeneity and functional (e.g., transcriptomic) consequences of extrachromosomal DNA on tumors. To address this, we introduce scAmp: a probabilistic algorithm for detecting and analyzing extrachromosomal DNA from single-cell datasets. Using well-characterized cell lines, we demonstrate that scAmp has improved specificity over bulk genome sequencing in predicting extrachromosomal DNA status and can resolve the status of chromosomal amplifications that were historically extrachromosomal. We further showcase scAmp by analyzing 73 patient tumors profiled with single-cell assay for transposase-accessible chromatin by sequencing, where we characterize the subclonal evolution of subclones with extrachromosomal DNA and identify the effect of these amplifications on the chromatin accessibility landscape of cancer cells. Finally, we provide proof-of-concept analyses that scAmp aids in the detection of extrachromosomal DNA from clinical histopathology assays. Together, we anticipate that scAmp will broadly enable further studies - both retrospective and prospective - that dissect critical questions of how extrachromosomal DNAs affect cancer cells and the tumors in which they reside.

Humans↗

PubMed2026

Detecting and reconstructing breakage-fusion-bridge cycles from long-read sequencing using BFBArchitect.

MOTIVATION: Focal oncogene amplification is a key driver of tumor progression. Remarkably, the increased pathology depends on the context-whether the amplification is extrachromosomal (ecDNA) or intrachromosomal. EcDNA amplifications promote heterogeneity, therapy resistance, and poor prognosis. Focal intrachromosomal amplifications often arise through breakage-fusion-bridge (BFB) cycles, which produce highly rearranged but stable chromosomes. Distinguishing BFB from ecDNA remains challenging due to overlapping genomic signatures. To address this, we present BFBArchitect, a computational method leveraging long-read Oxford Nanopore data to identify BFB sequences consistent with both copy number and structural variations. RESULTS: We provide a novel combinatorial characterization of BFB, which naturally leads to an integer linear programming (ILP) optimization. The ILP optimization generates a BFB sequence that best explains experimentally observed copy numbers and foldback structural variants. We implement this idea in a tool called BFBArchitect, which achieves near-perfect accuracy in distinguishing BFB from non-BFB structures in extensive simulations as well as on 18 validated tumor samples. Moreover, it generates sequence-level BFB reconstructions that provide mechanistic insights into BFB formation, including repair mechanisms with template switching and other structural variants, and recapture of telomere for stabilization. AVAILABILITY AND IMPLEMENTATION: BFBArchitect is available at https://github.com/AmpliconSuite/BFBArchitect.

Sequence Analysis, DNA↗

PubMed2025

Enhancer activation from transposable elements in extrachromosomal DNA.

Extrachromosomal DNA (ecDNA) drives oncogene amplification and intratumoral heterogeneity in aggressive cancers. While transposable element (TE) reactivation is common in cancer, its role on ecDNA remains unexplored. Here, we map the 3D architecture of MYC-amplified ecDNA in colorectal cancer cells and identify 68 ecDNA-interacting elements (EIEs)-genomic loci enriched for TEs that are frequently integrated onto ecDNA. We focus on an L1M4a1#LINE/L1 fragment co-amplified with MYC, which functions only in the ecDNA amplified context. Using CRISPR-CATCH, CRISPR interference, and reporter assays, we confirm its presence on ecDNA, enhancer activity, and essentiality for cancer cell fitness. These findings reveal that repetitive elements can be reactivated and co-opted as functional rather than inactive sequences on ecDNA, potentially driving oncogene expression and tumor evolution. Our study uncovers a mechanism by which ecDNA harnesses repetitive elements to shape cancer phenotypes, with implications for diagnosis and therapy.

Journal Article↗

PubMed2025

Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment.

Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA.

Journal Article↗