Biology subjects

Berg, T. J.

Publications and source records attributed to Berg, T. J..

5 recordsLinked to original sources

bioRxiv2026

Optimized dosing of spatially heterogeneous radiopharmaceutical therapy reprograms poorly immunogenic tumors to enhance response to immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are ineffective in patients with poorly immunogenic tumors due to exclusion or exhaustion of effector T cells in the tumor microenvironment (TME) and/or inadequate priming of tumor-specific T cells. Preclinical and clinical studies suggest that radiopharmaceutical therapy (RPT) may overcome such challenges, but an optimal approach to RPT dosing has not been clarified in combination with ICIs. Conventional RPT dosimetry emphasizes mean absorbed radiation doses in tumors and normal tissues, neglecting the spatial distribution of this dose in the TME. We hypothesize that RPT dose heterogeneity in tumors may be leveraged to initiate spatially restricted immuno-radiobiological effects in TME that potentiate antitumor immunity when injecting an activity that delivers high dose (V10%>20 Gy) while also preserving low dose regions (V90%<2.5 Gy) in the TME and not inducing systemic lymphopenia. In studies using lutetium-177 RPT in combination with ICIs, administered activities that met these dosimetric optimization metrics occurred at different mean tumor doses for different RPT agents and different models, yet each achieved therapeutic efficacy in poorly immunogenic murine tumors. Spatial transcriptomics at day 7 after RPT revealed heterogeneous distribution of tumor cell markers with distinct dose-response profiles and localization of dendritic cell (DC) migratory markers in regions of moderate/high dose response marker expression. Combination therapy sustained conventional type 1 DC (cDC1) activation in tumor draining lymph nodes and promoted systemic expansion of antigen-specific CD8 T cells, while serial biopsies revealed effector T cell recruitment and inflammatory cytokine expression in the TME. Optimized intratumoral dose heterogeneity may enable and predict response to ICIs when combined with RPT in tumors not responding adequately to ICIs alone.

cancer biology↗

bioRxiv2026

Intratumoral dose heterogeneity promotes adaptive anti-tumor immunity and predicts clinical response to radiopharmaceutical therapy

Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering <2.5 Gy to >20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8+ T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.

cancer biology↗

bioRxiv2025

Phenotypic Screening Identifies Flunarizine as an Inhibitor of Radiotherapy-Induced Astrocyte Reactivity with Therapeutic Potential in Glioblastoma

Radiotherapy is part of the standard-of-care for glioblastoma, yet tumors invariably recur as incurable lesions post-treatment. Recent studies suggest that radiation-induced astrocyte reactivity fosters a tumor-supportive environment, however effective strategies targeting reactive astrocyte phenotypes are lacking. Using a novel image-based assay, we screened over 1,700 small molecule compounds, identifying 29 that inhibit radiation-induced astrocyte reactivity in human astrocytes. Among these, Flunarizine, a calcium-entry blocker approved for migraine treatment, significantly reduced astrocyte reactivity in vitro and in vivo. In a genetically engineered glioblastoma mouse model, combining Flunarizine with radiotherapy markedly improved survival without affecting unirradiated controls, indicating specificity for a radiation-induced phenotype. Mechanistically, Flunarizine inhibited radiation-induced fibrosis in vivo and directly suppressed astrocytic TGF-beta activation in vitro. Notably, Flunarizine treatment had no direct effect on primary glioblastoma cells, emphasizing its microenvironmental specificity. In conclusion, we identified Flunarizine as a promising repurposed compound capable of effectively mitigating radiation-induced astrocyte reactivity and delaying glioblastoma recurrence. This approach offers a viable therapeutic strategy to enhance current glioblastoma treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/664538v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@d4d0d6org.highwire.dtl.DTLVardef@1dac551org.highwire.dtl.DTLVardef@1d071ccorg.highwire.dtl.DTLVardef@1df1a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Niche-derived soluble DLK1 promotes glioma stemness and growth

Tumor cell behaviors associated with aggressive tumor growth such as proliferation, therapeutic resistance, and stemness are regulated in part by soluble factors derived from the tumor microenvironment. Tumor-associated astrocytes represent a major component of the glioma tumor microenvironment, and astrocytes have an active role in maintenance of normal neural stem cells in the stem cell niche, in part via secretion of soluble Delta-like Non-Canonical Notch Ligand 1 (DLK1). We found that astrocytes, when exposed to stresses of the tumor microenvironment such as hypoxia or ionizing radiation (IR), increased secretion of soluble DLK1. Tumor-associated astrocytes in a glioma mouse model expressed DLK1 in perinecrotic (hypoxic) and perivascular tumor areas. Glioma cells exposed to recombinant DLK1 displayed increased proliferation, enhanced sphere and colony formation abilities, and increased levels of stem cell marker genes. Mechanistically, DLK1-mediated effects on glioma cells involved increased and prolonged stabilization of Hypoxia-Inducible Factor 2alpha (HIF-2alpha), and inhibition of HIF-2alpha activity abolished effects of DLK1 in hypoxia. Forced expression of soluble DLK1 resulted in more aggressive tumor growth and shortened survival in a genetically engineered mouse model of glioma. Together, our data support DLK1 as a soluble mediator of glioma aggressiveness derived from the tumor microenvironment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/258608v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@18902b8org.highwire.dtl.DTLVardef@11b21corg.highwire.dtl.DTLVardef@1c44f60org.highwire.dtl.DTLVardef@1376300_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAstrocytes secrete DLK1 after exposure to hypoxia or irradiation C_LIO_LISoluble DLK1 promotes stemness in glioma, in part by increasing HIF-2alpha stabilization. C_LIO_LIHigh levels of soluble DLK1 are associated with tumor aggressiveness and lethality. C_LI

cancer biology↗

bioRxiv2020

The irradiated brain microenvironment supports glioma stemness and survival via astrocyte-derived Transglutaminase 2

The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance, and following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here, we found that astrocytes, when pre-irradiated, increased stemness and survival of co-cultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. We identified extracellular matrix derived from irradiated astrocytes as a major driver of this phenotype, and astrocyte-derived transglutaminase 2 (TGM2) as a promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard of care radiotherapy by reducing stemness in glioma.

cancer biology↗