Biology subjects

Hoffmann, D. C.

Publications and source records attributed to Hoffmann, D. C..

3 recordsLinked to original sources

bioRxiv2025

Decoding Plasticity Regulators and Transition Trajectories in Glioblastoma with Single-cell Multiomics

Glioblastoma (GB) is one of the most lethal human cancers, marked by profound intratumoral heterogeneity and near-universal treatment resistance. Cellular plasticity, the capacity of cancer cells to transition between phenotypic states, drives GB progression and resistance. However, the regulatory logic that permits or restricts specific state transitions remains poorly understood. Here, we integrated single-nucleus RNA and chromatin accessibility multi-ome profiles from over one million cells across primary IDH-wildtype GBs and developed scDORI, a scalable deep-learning framework to infer enhancer-driven gene regulatory networks (eGRNs) at single-cell resolution. Our analysis revealed a structured hierarchy of GB cell states governed by distinct regulatory programs, with marked variability in epigenetic plasticity that enables or constrains transitions. Neuronal-like tumor cells emerge as a low plasticity state that deploys active repression, in contrast to more permissive progenitor-like and astrocytic states. We identified the neuronal-like state-specific repressor MYT1L as a key regulator that silences master transcription factors of alternative states. MYT1L gain-of-function in patient-derived GB cells reduced chromatin accessibility, induced neuronal-like identity, and restricted proliferation and invasion in vivo, whereas loss-of-function reactivated plasticity and accelerated malignant features. Our findings delineate the epigenetic architecture and associated transcriptional master regulators that shape GB state trajectories, and establish safeguard repressors such as MYT1L as potential therapeutic targets to constrain malignant plasticity.

cancer biology↗

bioRxiv2024

Molecular recording of cellular protein kinase activity with chemical labeling

Protein kinases control most cellular processes and aberrant kinase activity is involved in numerous diseases. To investigate the link between specific kinase activities and cellular phenotypes in heterogeneous cell populations and in vivo, we introduce molecular recorders of kinase activities for later analysis. Based on split-HaloTag and a phosphorylation-dependent molecular switch, our recorders become rapidly labeled in the presence of a specific kinase activity and a fluorescent HaloTag substrate. The kinase activity in a given cell controls the degree of fluorescent labeling whereas the recording window is set by the presence of the fluorescent substrate. We have designed specific recorders for four protein kinases, including protein kinase A. We apply our protein kinase A recorder for the sorting of heterogeneous cell populations and subsequent transcriptome analysis, in genome-wide CRISPR screens to discover regulators of PKA activity and for the tracking of neuromodulation in freely moving mice.

biochemistry↗

bioRxiv2021

A connectivity signature for glioblastoma

Tumor cell extensions called tumor microtubes (TMs) in glioma resemble neurites during neurodevelopment and connect glioma cells to a network that has considerable relevance for tumor progression and therapy resistance. The determination of interconnectivity in individual tumors has been challenging and the impact of tumor cell connectivity on patient survival remained unresolved so far. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells was established and clinically validated. Thirty-four of 40 connectivity genes were related to neurogenesis, neural tube development or glioma progression, including the TM-network-relevant GAP43 gene. Astrocytic-like and mesenchymal-like GB cells had the highest connectivity signature scores in scRNA-Seq data of patient-derived xenografts and patient samples. In 230 human GBs, high connectivity correlated with the mesenchymal expression subtype, TP53 wildtype, and with dismal patient survival. CHI3L1 was identified as a robust molecular marker of connectivity. Thus, the connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell connectivity is relevant for patients prognosis, and serves as a robust biomarker that can be used for future clinical trials. Statement of significanceIntegration of GB cells into functional networks drives tumor progression and resistance. Here, we established and validated a novel connectivity gene expression signature of single GB cells and whole tumors that can be easily applied to clinical and preclinical samples. It is shown that connectivity is determining prognosis combining molecular, functional and clinical insights into the disease.

cancer biology↗