Biology subjects

Przybilla, M. J.

Publications and source records attributed to Przybilla, M. J..

4 recordsLinked to original sources

bioRxiv2026

Persistence of tobacco-mutated alveolar progenitor cells after smoking cessation mirrors long term risk of lung adenocarcinoma

Tobacco smoke shapes mutations, selection and clonal expansion in lung epithelial cells. Smoking cessation leads to divergent epidemiology in the two most common lung cancers: squamous cell carcinoma risk declines sharply, while adenocarcinoma risk is preserved. To investigate this discrepancy, we analysed 806 genomes of alveolar type II (AT2) cells and found persistently elevated mutation burdens after cessation. In contrast, in the proximal airway, rare basal stem cells with near-normal mutation burden expand after cessation, protecting against squamous cell carcinoma. Targeted single-molecule DNA sequencing of AT2 cells revealed positive selection for TP53 and cell cycle and MAPK genes, supporting continued cancer risk. A multistage carcinogenesis model emphasised the importance of a small population of hypermutated cells in the alveoli and reproduced the divergent epidemiological trajectories following cessation due to distinct regenerative dynamics. Our findings suggest that differences in mutational burden and clonal regeneration explain post-cessation trends in lung cancer subtypes. One sentence summaryCancer risk reflects not only cumulative exposure to toxins, but the capacity of tissues to erase genomic damage through regeneration from protected cells with clonal advantage.

genomics↗

bioRxiv2022

Experimental evolution in TP53 deficient gastric organoids recapitulates tumorigenesis

The earliest events during human tumor initiation, while poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult pre-neoplasia by bi-allelically inactivating TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over two years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single cell sequencing of TP53 deficient gastric organoids similarly indicates progression towards malignant transcriptional programs. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programs repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference, and a striking degree of phenotypic convergence in pre-malignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and reveal evolutionary constraints and barriers to malignant transformation with implications for earlier detection and interception of aggressive, genome instable tumors.

cancer biology↗

bioRxiv2021

Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability

Chromothripsis is a form of genome instability, whereby a presumably single catastrophic event generates extensive genomic rearrangements of one or few chromosome(s). However, little is known about the heterogeneity of chromothripsis across different clones from the same tumor, as well as changes in response to treatment. We analyzed single-cell genomic and transcriptomic alterations linked with chromothripsis in human p53-deficient medulloblastoma (n=7). We reconstructed the order of somatic events, identified early alterations likely linked to chromothripsis and depicted the contribution of chromothripsis to malignancy. We characterized subclonal variation of chromothripsis and its effects on double-minute chromosomes, cancer drivers and putatively druggable targets. Furthermore, we highlighted the causative role and the fitness consequences of specific rearrangements in neural progenitors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/449944v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@9d30e4org.highwire.dtl.DTLVardef@1f4d34eorg.highwire.dtl.DTLVardef@5cd50corg.highwire.dtl.DTLVardef@a71a81_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

The shared neoantigen landscape of MSI cancers reflects immunoediting during tumor evolution

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are particularly abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. The abundance of mutational neoantigens renders MSI cancers sensitive to immune checkpoint blockade. However, the neoantigen landscape of MMR-deficient cancers has not yet been systematically mapped. In the present study, we used a novel tool to monitor neoantigen-inducing indel mutations in MSI colorectal and endometrial cancer. Our results show that MSI cancers share several highly immunogenic neoantigens that result from specific, recurrent indel mutation events. Notably, the frequency of such indel mutations was negatively correlated to the predicted immunogenicity of the resulting neoantigens. These observations suggest continuous immunoediting of emerging MMR-deficient cells during tumor evolution.\n\nOne sentence summaryQuantitative indel mutation analysis reveals evidence of immune selection in mismatch repair-deficient cancers

cancer biology↗