Biology subjects

Yu, K. K. H.

Publications and source records attributed to Yu, K. K. H..

4 recordsLinked to original sources

bioRxiv2026

Evolution of oncogene amplification across 86,000 cancer cell genomes

High-level copy-number (CN) amplification (HLAMP) is a major mechanism of oncogene activation in human cancer. Despite progress in therapeutically targeting amplified oncogenes, the processes underlying amplicon evolution remain incompletely understood, leaving critical knowledge gaps in their etiology and mechanisms of therapeutic response. To address this, we analyzed the evolutionary trajectories of HLAMPs using single-cell whole-genome sequencing data from 86,239 cancer cells across 93 patients and 9 experimental systems. We found that cell-to-cell CN variability provides a quantifiable readout of HLAMP mechanism, clearly distinguishing extrachromosomal circular DNA (ecDNA) from intrachromosomal amplification (ICamp) through characteristic CN distributions that reflect distinct modes of segregation and correspond to clonal architecture. Notably, ICamp events frequently showed multiple amplitude peaks specific to subclones, indicating punctuated shifts in oncogene dosage through numeric or structural modulatory mechanisms with transcriptional impact. In contrast, ecDNAs exhibited broad, continuous CN distribution with extreme high-copy outliers, consistent with asymmetric segregation. The CN and structural diversity of ecDNA regions enabled systematic deconvolution of ecDNA subspecies and estimation of their per-cell abundance, revealing the history of ecDNA-mediated oncogenesis at single-nucleotide resolution. We observed ecDNA diversification through internal rearrangements across cases and, notably, convergent evolution in glioblastoma cases marked by multiple, recurrent acquisition of EGFR-targeting ecDNAs. Finally, single-cell genome-based identification of ecDNAs showed substantial discrepancy with bulk genome graph-based predictions and reliably distinguished actively maintained ecDNAs from historical genomic footprints after chromosomal re-integration. These findings reveal marked tissue-type specificity of ecDNAs, suggesting that ecDNA-mediated oncogenesis may depend on a permissive tissue context.

genomics↗

bioRxiv2025

Mechanoimmunological Control of Metastatic Site Selection

Cancer cells alter their mechanical properties in response to the rigidity of their environment. Here, we explored the implications of this environmental mechanosensing for anti-tumor immunosurveillance using single cell biophysical profiling and metastasis models. Cancer cells stiffened in more rigid environments, a biophysical change that sensitized them to cytotoxic lymphocytes. In immunodeficient mice, this behavior manifested in the outgrowth of stiffer metastatic cells in the rigid bone than in the soft lung, while in immunocompetent hosts, it led to preferential elimination of stiffer cancer cells and suppression of bone metastasis. Environmentally-induced cell stiffening and immune sensitization both required Osteopontin, a secreted glycoprotein that is upregulated during bone colonization. Analysis of patient metastases spanning mechanically distinct tissues revealed associations between environmental rigidity, immune infiltration, and cancer cell stiffness consistent with mechanically driven immunosurveillance. These results demonstrate how environmental mechanosensing modulates anti-tumor immunity and suggest a mechanoimmunological basis for metastatic site selection.

cancer biology↗

bioRxiv2025

A pathogenic subpopulation of human glioma associated macrophages linked to glioma progression

Malignant gliomas follow two distinct natural histories: de novo high grade tumors such as glioblastoma, or lower grade tumors with a propensity to transform into high grade disease. Despite differences in tumor genotype, both entities converge on a common histologically aggressive phenotype, and the basis for this progression is unknown. Glioma associated macrophages (GAM) have been implicated in this process, however GAMs are ontologically and transcriptionally diverse, rendering isolation of pathogenic subpopulations challenging. Since macrophage contextual gene programs are orchestrated by transcription factors acting on cis-acting promoters and enhancers in gene regulatory networks (GRN), we hypothesized that functional populations of GAMs can be resolved through GRN inference. Here we show via parallel single cell RNA and ATAC sequencing that a subpopulation of human GAMs can be defined by a GRN centered around the Activator Protein-1 transcription factor FOSL2 preferentially enriched in high grade tumors. Using this GRN we nominate ANXA1 and HMOX1 as surrogate cell surface markers for activation, thus permitting prospective isolation and functional validation in human GAMs. These cells, termed malignancy associated GAMs (mGAMs) are pro-invasive, pro-angiogenic, pro-proliferative, possess intact antigen presentation but skew T-cells towards a CD4+FOXP3+ phenotype under hypoxia. Ontologically, mGAMs share somatic mitochondrial mutations with peripheral blood monocytes, and their presence correlates with high grade disease irrespective of underlying tumor mutation status. Furthermore, spatio-temporally mGAMs occupy distinct metabolic niches; mGAMs directly induce proliferation and mesenchymal transition of low grade glioma cells and accelerate tumor growth in vivo upon co-culture. Finally mGAMs are preferentially enriched in patients with newly transformed regions in human gliomas, supporting the view that mGAMs play a pivotal role in glioma progression and may represent a plausible therapeutic target in human high-grade glioma.

cancer biology↗

bioRxiv2024

Transcript-specific enrichment enables profiling rare cell states via scRNA-seq

Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing (scRNA-seq) identifies many rare populations of interest that express specific marker transcript combinations, traditional flow sorting limits our ability to enrich these populations for further profiling, including requiring cell surface markers with high-fidelity antibodies. Additionally, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. To address these limitations, we describe Programmable Enrichment via RNA Flow-FISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations from complex cellular mixtures defined by the presence or absence of specific RNA transcripts. Across immune populations (n = 141,227 cells) and fresh-frozen and formalin-fixed paraffin-embedded brain tissue (n = 29,522 nuclei), we demonstrate the sorting logic that can be used to enrich for cell populations via RNA-based cytometry followed by high-throughput scRNA-seq. Our approach provides a rational, programmable method for studying rare populations identified by one or more marker transcripts.

genomics↗