Biology subjects

Roelz, R.

Publications and source records attributed to Roelz, R..

4 recordsLinked to original sources

bioRxiv2026

Spatially confined niches support hypoxia-associated transcriptional plasticity contributing to malignant progression in IDH-mutant gliomas

BackgroundWhile hypoxia is a well-established driver of glioblastoma progression, its role in IDH-mutant gliomas, characterized by localized hypoxic microenvironments rather than overt necrosis, remains poorly understood. Here, we investigate how hypoxia and microenvironmental-adaptations shape cellular heterogeneity and transcriptional plasticity in these tumors. MethodsWe integrated bulk, single-cell, and spatial-transcriptomics datasets from IDH-mutant glioma patients (Astrocytomas and Oligodendrogliomas) to characterize cellular-states and map the localization of hypoxic niches. To uncover tumor microenvironment effects, we established co-culture models using primary IDH-mutant glioma cells with human microglia and astrocytes, maintained under hypoxic and normoxic conditions, followed by bulk RNA-sequencing. ResultsWe identified a hypoxia-associated astrocyte-like (AC-like) program that defines a quiescent, non-cycling population with a distinct transcription factor profile indicative of functional plasticity in IDH-mutant gliomas. These cells harbor glioma stem cell (GSC)-like features and are poised for a quiescent-to-activated (Q-to-A) transition that drives tumor progression. Mechanistically, co-culture models reveal that microglia promote this Q-to-A transition by enhancing HBEGF/EGFR paracrine signaling. Spatial transcriptomics uncovers the co-localization of hypoxic niches within quiescent AC-like cells, whereby the activated subpopulation forms discrete niches defined by localized HBEGF/EGFR communication gradients. Notably, tumors exhibiting elevated EGFR-driven activation signatures correlate with higher histological grade and poorer patient survival, implicating the Q-to-A transition as a critical driver of malignant progression. ConclusionQ-to-A transition within the hypoxic niche represents a critical driver of malignant progression in IDH-mutant gliomas, providing a microenvironment-driven mechanism for the transition to higher-grade disease and identifying targetable-vulnerabilities for therapeutic intervention. Key pointsO_LIHypoxic niches spatially confine quiescent, astrocyte-like cellular state characterized by glioma stem cell features in IDH-mutant gliomas. C_LIO_LIMicroglia triggers the quiescent-to-activated (Q-to-A) transition via paracrine EGFR signaling crosstalk. C_LIO_LIEGFR-driven Q-to-A plasticity serves as a microenvironmentally-regulated driver of malignant progression and adverse patient survival. C_LI Importance of the studyWhile high-grade glioblastomas feature well-defined hypoxic and necrotic regions that drive tumor progression and therapy resistance, IDH-mutant gliomas lack these distinct hallmarks, instead exhibiting disorganized hypoxic niches. Consequently, the functional contribution of these niches to tumor progression has remained poorly understood. Although genetic and epigenetic alterations are established drivers of progression in IDH-mutant gliomas, we provide an additional, essential layer of complexity: microenvironment-driven transcriptional plasticity. By uncovering the relationship between tumor hypoxia and heterogeneous glioma cell states, we uncover that these niches are essential for such plasticity. We also show that the tumor microenvironment provides critical molecular cues necessary to initiate a transcriptional shift enabling glioma cells to transition from a quiescent reservoir into an activated state primed for rapid proliferation. By identifying this paracrine mechanism, our work uncovers a targetable vulnerability that dictates how dormant cell reservoirs are mobilized to fuel malignant transformation.

cancer biology↗

bioRxiv2026

Hypoxia and Associated Acidosis Generate Cell-Type Specific Myeloid Responses in Glioblastoma

Hypoxia is a defining feature of glioblastoma (GBM), yet how it cooperates with hypoxia-associated acidosis to shape microglia and infiltrating monocyte-derived macrophages (MDM) remains poorly understood. We integrated cyclic immunohistochemistry, single-cell RNA sequencing, spatial transcriptomics, in vitro cell cultures, and DNA methylation profiling to outline hypoxia-driven responses in up to 136 GBMs. These hypoxic niches were selectively enriched for MDMs that activated carbonic anhydrase (CA) mediated pH buffering and other metabolic adaptation programs, enabling survival in acidic hypoxia, increasingly interacted with cancer cells, and show polarization toward immunosuppressive myeloid-derived suppressor cell (MDSC)-like states. In contrast, microglia were depleted in hypoxic areas, lacked compensatory CA isoenzymes, and developed TNF-linked stress responses and loss of homeostatic identity in acidic hypoxia. These findings identify metabolic adaptation to hypoxia-associated microenvironmental stress as a key determinant of GBM immune architecture, driving myeloid cell fates, spatial TME reorganization and the emergence of immunosuppressive tumor ecosystems.

cancer biology↗

bioRxiv2025

Iron-Associated Mesenchymal Plasticity and Tumor Invasion in Glioblastoma

Glioblastoma (GBM) recurrence is driven by tumor cells that infiltrate surrounding brain tissue and evade surgical and therapeutic eradication. Although dysregulated iron handling is a recognized feature of the necrotic and hemorrhagic GBM tumor core, its relationship to invasive tumor cell states remains incompletely defined. Here, we investigated how iron-associated microenvironments relate to transcriptional programs of invasion in human GBM. Using multi-regional single-nucleus RNA sequencing of human GBM specimens encompassing tumor core, invasive front, and infiltrated cortex, we found that malignant cells from the tumor core exhibit coordinated upregulation of iron uptake and storage pathways together with invasion-associated gene programs. At the single-cell level, iron metabolism and invasion signatures were strongly correlated, defining a distinct core-enriched malignant subpopulation with mesenchymal-like transcriptional identity, stress-adaptive features, and angiogenic signaling. These iron-high/invasion-high cells aligned with mesenchymal-and astrocyte-like GBM states and were associated with unfavorable patient survival. Despite elevated oxidative stress and ferroptosis-associated transcriptional pressure, this population concurrently expressed anti-apoptotic and anti-ferroptotic regulators, consistent with an iron-tolerant invasive state. To assess functional consequences of iron exposure, we modeled iron-rich conditions using non-cytotoxic particulate iron in patient-derived GBM cell lines and human organotypic cortical slice cultures. Iron exposure induced intracellular iron accumulation, oxidative stress responses, increased tumor cell motility in vitro, and enhanced invasion within intact human brain tissue. Collectively, these findings demonstrate that iron-rich tumor core niches are closely associated with mesenchymal plasticity and invasive behavior in GBM and support a role for iron-associated microenvironmental pressure in shaping invasive tumor cell states. Key PointsO_LITranscriptional profiling reveals that the GBM tumor core harbors malignant cells that strictly couple active iron metabolism with invasive programs. C_LIO_LIThis iron-accumulating, Mesenchymal-like subpopulation is distinctively characterized by angiogenesis and stress resistance. C_LIO_LIIron supplementation in vitro and human ex vivo models are sufficient to drive mesenchymal transition and significantly enhance tumor migration and tissue invasion. C_LI Importance of the StudyGlioblastoma (GBM) recurrence is driven by highly invasive tumor cells that evade resection and resist therapy. Yet the microenvironmental pressures that push GBM cells into an invasive, therapy-resistant state remain poorly defined. Although iron dysregulation has been implicated across cancers, its role as a microenvironmental determinant of GBM invasion has never been demonstrated in physiologically relevant human systems. By integrating multi-regional single-nucleus RNA sequencing with functional validation in patient-derived GBM lines and human organotypic cortical slice cultures, we uncover a core-enriched, iron-associated mesenchymal program that co-segregates with invasion, stress adaptation, and angiogenic signaling. We further show that physiologically relevant iron exposure is sufficient to induce mesenchymal transition, enhance motility, and accelerate tissue invasion within human cortical architecture. These findings position iron as a selective driver that links the hemorrhagic, necrotic GBM core to the emergence of invasive subpopulations that seed recurrence. The data identify iron handling and stress-response pathways as actionable therapeutic vulnerabilities, providing a foundation for strategies that target metabolic resilience and iron-dependent invasive states in GBM. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/695920v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@141cc11org.highwire.dtl.DTLVardef@bcb055org.highwire.dtl.DTLVardef@1dcd332org.highwire.dtl.DTLVardef@ad7cad_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Oncogenic RAS-Pathway Activation Drives Oncofetal Reprogramming and Creates Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis1. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins2-6. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease7-10. To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo. In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. Highlights{blacksquare} Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. {blacksquare}The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. {blacksquare}High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). {blacksquare}RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. {blacksquare}The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.

cancer biology↗