Biology subjects

Burns, T. C.

Publications and source records attributed to Burns, T. C..

6 recordsLinked to original sources

bioRxiv2026

Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma

IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.

cancer biology↗

bioRxiv2026

Functional genomics identifies therapeutic options, biomarkers, and resistance mechanisms for high-grade gliomas

High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/701806v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cdb75corg.highwire.dtl.DTLVardef@1c133e6org.highwire.dtl.DTLVardef@1365153org.highwire.dtl.DTLVardef@11543a4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Systems analysis uncovers early temozolomide responses and peptide antigens in glioblastoma

Temozolomide (TMZ) is the standard treatment for nearly all glioblastoma (GBM) patients, as it is the only chemotherapy shown to extend overall survival. However, this benefit is limited to a few months, underscoring the need for combination strategies to improve its efficacy. While TMZ-induced DNA damage can both mediate cytotoxicity and promote resistance, DNA damage more broadly can also stimulate immune activation. To evaluate its immunomodulatory potential, we characterized the previously unexplored early, cell-intrinsic consequences of TMZ in GBM cells, spanning DNA damage, stress responses, and antigen presentation. A multi-omics approach combining RNA sequencing and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) profiled changes in gene expression, nascent protein translation, steady-state protein levels, kinase-substrate phosphorylation patterns, and MHC-I peptide presentation in GBM cells within 72 hours of TMZ exposure. This analysis revealed rapid activation of DNA damage signaling and p53-associated stress pathways, alongside dynamic changes in protein synthesis and antigen presentation. A set of TMZ treatment-associated peptide antigens (TAPAs) was identified, including peptides derived from stress response proteins, phosphorylated MHC-I peptides, and those induced by other genotoxic treatments such as radiation. Several of these peptides were also detected in recurrent GBM patient tumors. Our findings suggest that TMZ not only triggers early adaptive and potentially resistance-associated stress programs but may also enhance the immune visibility of GBM cells. These data highlight potential windows for combination therapies with TMZ that bolster immune recognition of GBM, while the systems approach provides a framework to examine how genotoxic therapies across cancers alter tumor immunogenicity.

cancer biology↗

bioRxiv2021

Radiation-induced reprogramming drives glioma vascular transdifferentiation and tumor recurrence

Treatment-refractory glioma stem and tumor cells exhibit phenotypic plasticity driving recurrence, but the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide a trophic niche to promote proliferation of irradiated glioma cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation, and inhibits the phenotypic transition and tumor growth. Our findings highlight an important role for P300 histone acetyltransferase in treatment-induced plasticity and opens a new therapeutic avenue for preventing glioma recurrence. SignificanceOur study demonstrates that radiation therapy promotes glioma resistance by inducing vascular-like phenotypes in GSC that, in turn, aid in proliferation of the remaining tumor cells. This phenotype switch is mediated by P300 HAT, and inhibition of this enzyme is a potential therapeutic target for preventing glioma recurrence following radiation.

cancer biology↗

bioRxiv2021

Simons Collaborative Marine Atlas Project (Simons CMAP): an open-source portal to share, visualize and analyze ocean data

Simons Collaborative Marine Atlas Project (Simons CMAP) is an open-source data portal that interconnects large, complex, and diverse public data sets currently dispersed in different formats across different Oceanography discipline-specific databases. Simons CMAP is designed to streamline the retrieval of custom subsets of data, the generation of data visualizations, and the analyses of diverse data, thus expanding the power of these potentially underutilized data sets for cross-disciplinary studies of ocean processes. We describe a unified architecture that allows numerical model outputs, satellite products, and field observations to be readily shared, mined, and integrated regardless of data set size or resolution. A current focus of Simons CMAP is integration of physical, chemical, and biological data sets essential for characterizing the biogeography of key marine microbes across ocean basins and seasonal cycles. Using a practical example, we demonstrate how our unifying data harmonization plans significantly simplifies and allows for systematic data integration across all Simons CMAP data sets.

ecology↗

bioRxiv2020

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts.

ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6, 10, 12, 39, 46, 76, 123, 164, 196; total n=8-15, per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation. Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. ResultOf nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196); similar to previous observations with GBM 143. GBM 6 was also evaluated 6 months after fractionated radiation yielding similar results. However, two lines yielded prolonged survival in the pre-radiated brain (GBM 10, 12); GBM12 and 10 demonstrated the fastest baseline growth in the non-radiated brain; GBM 39, 123 whose rate of growth was not impacted by the radiated brain, demonstrated a an intermediate baseline growth rate between that of those positively and negatively impacted by the radiated brain microenvironment. No other clinical or molecular phenotype was found to consistently correlate with response to the radiated microenvironment. ConclusionAmong a total of 10 total human GBM lines evaluated to date, 60% induce faster mortality in a radiated microenvironment, and 20% induce slower mortality. These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.

cancer biology↗