Biology subjects

Tetzlaff, S. K.

Publications and source records attributed to Tetzlaff, S. K..

4 recordsLinked to original sources

bioRxiv2026

Local translation drives glioblastoma heterogeneity and tumor invasion

O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/722387v1_ufig1.gif" ALT="Figure 1"> View larger version (96K): org.highwire.dtl.DTLVardef@1da020corg.highwire.dtl.DTLVardef@1bc9b32org.highwire.dtl.DTLVardef@171198aorg.highwire.dtl.DTLVardef@43ce6f_HPS_FORMAT_FIGEXP M_FIG C_FIG Glioblastoma is characterized by diffuse brain invasion, yet the subcellular mechanisms enabling this aggressive behavior remain poorly understood. A subpopulation of glioblastoma cells forms invasive tumor microtubes (TMs), neurite-like extensions that drive whole-brain colonization. Here, we establish local protein translation as a fundamental driver of TM dynamics and invasive cell states. Developing a subcellular transcriptomics approach - integrating subcellular organelle organization with spatially resolved transcriptomics and functional readouts - we reveal that TM gene expression drives cell state identity. Invasive cells further exhibit significantly elevated local translation in protruding TMs, directly linking subcellular protein synthesis to functional invasive states associated with neurodevelopmental programs of axonal growth cones. Targeted disruption of TM-localized translation via photoswitchable puromycin, and specific knockdowns of the TM-enriched proteins GPM6A and GAP43, impaired TM dynamics, suppressed invasion, and reduced tumor growth. Together, these findings define local translation as a key determinant of tumor heterogeneity and glioblastoma invasion.

cancer biology↗

bioRxiv2024

Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types and segregate into molecularly and clinically distinct subgroups, suggesting different developmental roots. The developmental signatures as well as microenvironmental factors underlying aberrant cellular transformation and behavior across each supratentorial ependymoma subgroup are unknown. Here we integrated single cell- and spatial transcriptomics, as well as in vitro and in vivo live-cell imaging to define supratentorial ependymoma cell states, spatial organization, and dynamic behavior within the neural microenvironment. We find that individual tumor subgroups harbor two distinct progenitor-like cell states reminiscent of early human brain development and diverge in the extent of neuronal or ependymal differentiation. We further uncover several modes of spatial organization of these tumors, including a high order architecture influenced by mesenchymal and hypoxia signatures. Finally, we identify an unappreciated role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and invasion mechanisms. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumor heterogeneity in supratentorial ependymoma and its potential clinical implications.

cancer biology↗

bioRxiv2024

Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing

Glioblastomas are invasive brain tumors with high therapeutic resistance. Neuron-to-glioma synapses have been shown to promote glioblastoma progression. However, a characterization of tumor-connected neurons has been hampered by a lack of technologies. Here, we adapted retrograde tracing using rabies viruses to investigate and manipulate neuron-tumor networks. Glioblastoma rapidly integrated into neural circuits across the brain engaging in widespread functional communication, with acetylcholinergic neurons driving glioblastoma invasion. We uncovered patient-specific and tumor cell state-dependent differences in synaptogenic gene expression associated with neuron-tumor connectivity and subsequent invasivity. Importantly, radiotherapy enhanced neuron-tumor connectivity by increased neuronal activity. In turn, simultaneous neuronal activity inhibition and radiotherapy showed increased therapeutic effects, indicative of a role for neuron-to-glioma synapses in contributing to therapeutic resistance. Lastly, rabies-mediated genetic ablation of tumor-connected neurons halted glioblastoma progression, offering a viral strategy to tackle glioblastoma. Together, this study provides a framework to comprehensively characterize neuron-tumor networks and target glioblastoma.

cancer biology↗

bioRxiv2023

Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis

Intravital two-photon microscopy has emerged as a powerful technology to study brain tumor biology and its temporal dynamics, including invasion, proliferation and therapeutic resistance in the superficial layers of the mouse cortex. However, intravital microscopy of deeper cortical layers and especially the subcortical white matter, an important route of glioblastoma invasion and recurrence, has not yet been feasible due to low signal-to-noise ratios, missing spatiotemporal resolution and the inability to delineate myelinated axonal tracts. Here, we present a tailored intravital microscopy and artificial intelligence-based analysis methodology and workflow that enables routine deep imaging of glioblastoma over extended time periods, named Deep3P. We show that three-photon microscopy, adaptive optics, as well as customized deep learning-based denoising and machine learning segmentation together allow for deep brain intravital investigation of tumor biology up to 1.2 mm depth. Leveraging this approach, we find that perivascular invasion is a preferred invasion route into the corpus callosum as compared to intracortical glioblastoma invasion and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we can define an imaging biomarker of white matter disruption during early glioblastoma colonization. Taken together, Deep3P allows for an efficient and non-invasive investigation of brain tumor biology and its tumor microenvironment in unprecedented deep white and gray matter of the living mouse, opening up novel opportunities for studying the neuroscience of brain tumors and other model systems.

cancer biology↗