SEARCH · bioRxiv Science

Results for “Cancer Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 829 records · Page 46Linked to original sources

bioRxiv2023

Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. HighlightsO_LIPeriventricular GBM is more malignant and disrupts neurogenesis in a rodent model. C_LIO_LICell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs. C_LIO_LINPCs induce upregulated CTSB expression in GBM, promoting tumor progression. C_LIO_LIGBM stalls neurogenesis and promotes NPC senescence via CTSB. C_LI

cancer biology↗

bioRxiv2019

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.\n\nSignificance StatementMeningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.

cancer biology↗

bioRxiv2023

A first comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas.

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new tumor enhancer. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

cancer biology↗

bioRxiv2024

IKZF2-ERBB4 gene fusion leads to ERBB4 overexpression in Anal Squamous Cell Carcinoma but with no benefit for ERBB4 inhibition

Anal squamous cell carcinoma (ASCC) is a rare tumour, but with increasing incidence for local and metastatic tumours. Current therapy is based on chemoradiotherapy, associated with immunotherapy in advanced stages, with frequent side effects, poor results in advanced stages and recurrence. New therapeutics, including targeted therapies, are then needed. In this context, we identified here a IKZF2-ERBB4 gene fusion in a patient ASCC tumour, leading to overexpressed mRNA encoding a functional ERBB4 protein. This gene fusion has been already reported in other tumour types but not yet investigated as therapeutical target. The matched patient tumour-derived xenograft displays the same gene fusion and mRNA overexpression. It provided biological material for anti-ERBB4 testing in different cell models (in vivo xenograft, in vitro cell cultures). We used afatinib and lapatinib, 2 chemical pan-ERBB inhibitors approved in clinics, with anti-ERBB4 properties. ERBB4 inhibition did not lead to tumour growth inhibition although afatinib and lapatinib dramatically decreased ERBB4 phosphorylation with impact on downstream signalling MAPK/ERK but not PI3K/AKT pathways. Likewise, specific ERBB4 knock-outing did not affect tumour cell proliferation. These negative results must be put in line with reported potential crosstalk between PI3K/AKT and MAPK/ERK pathways in therapeutic resistance.

cancer biology↗

bioRxiv2019

Differential and Age Dependent Expression of Specific Sialoglycans on HeLa Cells -Revealed by Direct Fluorescent Glycan Labeling

Cells are covered with glycans. The expression and distribution of specific glycans on cell surface are important for various cellular functions. Imaging these glycans is essential to elucidate their biological roles. Here, utilizing enzymatic incorporation of fluorophore-conjugated sialic acids, dubbed as direct fluorescent glycan labeling (DFGL), we report the imaging of N- and O-glycans and particularly tumor specific sialyl T antigen on HeLa cells. It is found that while Core-1 O-glycans are relatively evenly distributed on cells, the expression of N-glycans tend to be more peripheral. More interestingly, the expression of sialyl T antigen displays random and sporadic patterns. In technique side, DFGL allows convenient labeling or imaging of various glycans on intact glycoproteins or cell surfaces with variety of fluorescent dyes.

cancer biology↗

bioRxiv2018

Ribosomal protein imbalance launches a C/EBP-based program to preserve tissue integrity

Genes encoding ribosomal proteins are expressed at rate limiting levels, rendering their biological function highly sensitive to the copy-number variation that results from genomic instability. Cells with a reduced number of ribosomal protein genes (RPGs) are eliminated, when intermingled with wild type cells, via a process known as cell competition. The mechanisms underlying this phenomenon are poorly understood. Here we report the function of a CCAAT-Enhancer-Binding Protein (C/EBP), Xrp1, that is critically required for the elimination of cells with a hemizygous RPG genotype. In such cells, Xrp1 is transcriptionally upregulated by an autoregulatory loop and is able to trigger cell elimination. Since genomic instability is likely to cause the loss of a haploinsufficient RPG, we propose a molecular model of how RPGs, together with a C/EBP-dependent transcriptional program, could preserve the genomic integrity of tissues.

cancer biology↗

bioRxiv2026

CDK9 pharmacological inhibition with PRT2527 has antitumor activity in marginal zone lymphoma models and can improve the effects of BTK, PI3K, and BCL2 inhibitors

Cyclin-dependent kinase 9 (CDK9) drives transcriptional elongation and supports the expression of short-lived oncogenic and anti-apoptotic proteins such as MYC and MCL1. PRT2527 is a potent, selective CDK9 inhibitor currently in early clinical development. We evaluated its preclinical activity in marginal zone lymphoma (MZL) models, including cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors. Short exposure (4 hours) to PRT2527 produced nanomolar cytotoxicity across all tested MZL cell lines, with efficacy maintained in resistant derivatives. Transcriptomic profiling of VL51 cells showed broad gene repression, including MYC, IRF4, NF-{kappa}B-related genes, and MCL1, alongside increased expression of HLA class II genes. Moreover, comparison with additional CDK inhibitors revealed a similar transcriptional repression signature, underscoring a conserved CDK-dependent regulatory network. Protein analyses confirmed rapid depletion of MCL1, MYC, RNA polymerase II, and IRF4. Flow cytometry validated increased HLA class II and decreased HLA class I surface expression. Combination studies demonstrated additive to synergistic effects with BTK inhibition (ibrutinib) or dual PI3K/BCL2 inhibition (copanlisib plus venetoclax), independent of baseline drug sensitivity. Mechanistically, these combinations may enhance apoptosis by concurrently suppressing survival signaling and transcriptional addiction. Analysis of patient samples revealed high CDK9 expression, further supporting the biological relevance and therapeutic rationale for targeting CDK9 in this disease. Our findings support the development of CDK9-based combination strategies for relapsed/refractory MZL and other B-cell malignancies, with an additional potential for integration with immunotherapies. Key PointsO_LICDK9 inhibitor PRT2527 kills marginal zone lymphoma cells, regardless of whether they are resistant to other targeted drugs. C_LIO_LIPRT2527 boosts the effects of BTK, PI3K, and BCL2 inhibitors and alters immune-related gene expression. C_LI Draft of graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/705084v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@37b9e6org.highwire.dtl.DTLVardef@8de6a5org.highwire.dtl.DTLVardef@219771org.highwire.dtl.DTLVardef@15dabfe_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2013

U2AF1 mutations alter splice site recognition in hematological malignancies

Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1s zinc finger domains.

Cancer Biology↗

bioRxiv2025

A breast tissue-specific epigenetic clock provides accurate chronological age predictions and reveals de-correlation of age and DNA methylation in tumor-adjacent and tumor samples

Epigenetic clocks have been widely used to estimate biological age across various tissues, but their accuracy in breast tissue remains suboptimal. Pan-tissue models such as Horvaths and Hannums clocks, perform poorly in predicting chronological age in breast tissue, underscoring the need for a tissue-specific approach. In this study, we introduce a Breast Tissue-specific Epigenetic Clock (BTEC), developed using DNA methylation data from 553 healthy breast tissue samples across seven different studies. BTEC significantly outperformed pan-tissue clocks, demonstrating superior correlation with chronological age (r=0.88) and lower prediction errors (MAE=3.27 years) without requiring for dataset-specific regressions adjustments. BTECs chronological age predictions for tumor-adjacent samples showed distortions, with an average deviation of -1.76 years, which was even more pronounced in tumor samples, where the average difference between predicted and chronological age was -12.29 years. When analyzed by molecular subtype, the distortion was greater in the more aggressive HER2+ and TNBC tumors compared to HR+ tumors. The probes used by BTEC were associated with known oncogenes, genes involved in estrogen metabolism, cadherin binding and fibroblast growth factor binding. Despite the general rejuvenation observed in tumor tissue compared to normal breast, the correlation between BTECs predictions and cancer-related survival indicated that TNBC tumors with increased epigenetic ages had significant lower survival.

cancer biology↗

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↗

bioRxiv2023

Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma

High expression of MYC and its target genes define a subset of germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) associated with poor outcomes. Half of these high-grade cases show chromosomal rearrangements between the MYC locus and heterologous enhancer-bearing loci, while focal deletions of the adjacent non-coding gene PVT1 are enriched in MYC-intact cases. To identify genomic drivers of MYC activation, we used high-throughput CRISPR-interference (CRISPRi) profiling of candidate enhancers in the MYC locus and rearrangement partner loci in GCB-DLBCL cell lines and mantle cell lymphoma (MCL) comparators that lacked common rearrangements between MYC and immunoglobulin (Ig) loci. Rearrangements between MYC and non-Ig loci were associated with unique dependencies on specific enhancer subunits within those partner loci. Notably, fitness dependency on enhancer modules within the BCL6 super-enhancer (BCL6-SE) cluster regulated by a transcription factor complex of MEF2B, POU2F2, and POU2AF1 was higher in cell lines bearing a recurrent MYC::BCL6-SE rearrangement. In contrast, GCB-DLBCL cell lines without MYC rearrangement were highly dependent on a previously uncharacterized 3 enhancer within the MYC locus itself (GCBME-1), that is regulated in part by the same triad of factors. GCBME-1 is evolutionarily conserved and active in normal germinal center B cells in humans and mice, suggesting a key role in normal germinal center B cell biology. Finally, we show that the PVT1 promoter limits MYC activation by either native or heterologous enhancers and demonstrate that this limitation is bypassed by 3 rearrangements that remove PVT1 from its position in cis with the rearranged MYC gene. Key pointsO_LICRISPR-interference screens identify a conserved germinal center B cell MYC enhancer that is essential for GCB-DLBCL lacking MYC rearrangements. C_LIO_LIFunctional profiling of MYC partner loci reveals principles of MYC enhancer-hijacking activation by non-immunoglobulin rearrangements. C_LI

cancer biology↗

bioRxiv2024

H3F3A K27M Mutations Drives a Repressive Transcriptome by Modulating Chromatin Accessibility, Independent of H3K27me3 in Diffuse Midline Glioma

BackgroundHeterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase complex, leading to a global reduction and redistributing of the repressive H3 lysine 27 tri-methylation. This rewiring of the epigenome is thought to promote gliomagenesis. MethodsWe established novel, isogenic DMG patient-derived cell lines that have been CRISPR-Cas9 edited to H3.3 WT or H3.3K27M alone and in combination with EZH2 and EZH1 co-deletion, inactivating PRC2 methyltransferase activity of PRC2 and eliminating H3K27me3. ResultsRNA-seq and ATAC-seq analysis of these cells revealed that K27M has a novel epigenetic effect that appears entirely independent of its effects on PRC2 function. While the loss of the PRC2 complex led to a systemic induction of gene expression (including HOX gene clusters) and upregulation of biological pathways, K27M led to a balanced gene deregulation but having an overall repressive effect on the biological pathways. Importantly, the genes uniquely deregulated by the K27M mutation, independent of methylation loss, are closely associated with changes in chromatin accessibility, with upregulated genes becoming more accessible. Notably, the PRC2- independent function of K27M appears necessary for tumorigenesis as xenografts of our H3.3K27M/EZH1/2 WT cells developed into tumors, while H3.3/EZH1/2 KO cells did not. ConclusionWe demonstrate that K27M mutation alters chromatin accessibility and uniquely deregulates genes, independent of K27 methylation. We further show the mutations role in altering biological pathways and its necessity for tumor development. Key PointsO_LIWe revealed genes regulated by H3.3K27M mutation and PRC2 in DMG. C_LIO_LIH3.3K27M mutation alters chromosome accessibility independent of H3K27me3. C_LIO_LIPRC2-independent effects of K27M mutation are crucial for tumor development. C_LI Importance of the StudyThis study is the first to demonstrate that H3F3A K27M mutations drive a repressive transcriptome by modulating chromatin accessibility independently of H3K27 trimethylation in Diffuse Midline Glioma (DMG). By isolating the effects of H3.3 K27me3 loss from those of the K27M mutation, we identified common and unique genes and pathways affected by each. We found that genes uniquely deregulated by K27M showed increased chromatin accessibility and upregulated gene expression, unlike other gene subsets affected by PRC2 knockout. Importantly, we determined the PRC2-independent function of K27M is also essential for tumorigenesis, as xenografts of H3.3 K27M/PRC2 WT cell lines formed tumors, while H3.3WT/PRC2 WT and K27M/PRC2 knockout cells did not. This research builds upon and advances prior studies, such as those identifying EZH2 as a therapeutic target in H3.3K27M DMGs, by revealing critical new pathways for gliomagenesis. The translational significance lies in identifying novel therapeutic targets against this aggressive pediatric cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/594522v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@61edd6org.highwire.dtl.DTLVardef@145935dorg.highwire.dtl.DTLVardef@cde85aorg.highwire.dtl.DTLVardef@5184b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Modification of the microstructure of the CERN- CLEAR-VHEE beam at the picosecond scale modifies ZFE morphogenesis but has no impact on hydrogen peroxide production.

FLASH has emerged as a significant breakthrough for the future of radiation oncology, as it reduces complications while preserving the tumor killing efficacy. To define the beam parameters for future clinical translation, Very High Energy Electrons (VHEE) delivered at CLEAR and able to reach deep seated tumors were used in conjunction with a FLASH-validated Intermediate Energy Electron (IIE) beam and a 160-225 keV X-ray beam, collectively able to deliver dose rates spanning from 1 Gy/min to 1011 Gy/s. High-throughput chemical assays were used to investigate radiochemical effects of FLASH, while zebrafish embryos served as a model to evaluate its impact on biological outcomes and morphogenesis. This study is the first comprehensive exploration investigating the impact of a large range of dose rates and various temporal parameters from early physico-chemical events to a complex biological system. Data derived at CLEAR revealed that the intensity of the bunch is a critical factor for observing the sparing effect of FLASH and uncovered an unforeseen biological response when electrons are delivered over the picosecond timescale. Present data also suggests that scanning with high intensity beamlets will be optimal for the future clinical translation of FLASH. HighlightsTo investigate the physics parameters required to trigger the FLASH sparing effect, CLEAR/VHEE/CERN beam macro/microstructure was varied. We show that delivery at the picosecond scale: - reduces alteration in the morphogenesis of zebrafish embryos, but - has no impact on secondary hydrogen peroxide production, Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/629203v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1df896aorg.highwire.dtl.DTLVardef@b6b824org.highwire.dtl.DTLVardef@1f35964org.highwire.dtl.DTLVardef@171d60f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL

Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as \"molecular switches\" in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.

cancer biology↗

bioRxiv2023

Erythroid differentiation intensifies RNA mis-splicing in SF3B1-mutant myelodysplastic syndromes with ring sideroblasts

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly originate from mutations in the splicing factor SF3B1 (SF3B1mt). SF3B1mt cause RNA mis-splicing, mechanistically established as the major driver of RS development. However, little is known about RS fate and biology after their initial formation in the human bone marrow. We here achieve isolation of viable RS from patient samples, enabling the first complete investigation of SF3B1mt development from stem cell to RS. We show that RS skew MACS-isolated CD34+ data towards erythroid features not recapitulated in single-cell RNAseq. We demonstrate that RS divide, differentiate, enucleate and actively respond to mis-splicing/oxidative stress, decreasing wildtype stem cell fitness via GDF15 overproduction. We identify circulating RS as a uniform clinical feature associated with disease burden. Finally, we establish that SF3B1mt mis-splicing intensifies during erythroid differentiation and demonstrate through combined transcriptomics/proteomics an uncoupling of RNA/protein biology in RS encompassing severe and dysfunctional mis-splicing of proapoptotic genes. Statement of significanceWe here combine a novel method for RS isolation with state-of-the-art multiomics to perform the first complete investigation of SF3B1mt MDS-RS hematopoiesis from stem cell to RS. We identify the survival mechanisms underlying SF3B1mt erythropoiesis and establish an active role for erythroid differentiation and RS themselves in SF3B1mt MDS-RS pathogenesis.

cancer biology↗

bioRxiv2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, the most common intracranial tumor, though mostly benign can be recurrent and fatal. WHO grading does not always identify high risk meningioma and better characterizations of their aggressive biology is needed. To approach this problem, we combined 13 bulk RNA-Seq datasets to create a dimension-reduced reference landscape of 1298 meningiomas. Clinical and genomic metadata effectively correlated with landscape regions which led to the identification of meningioma subtypes with specific biological signatures. Time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape where nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcome. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

cancer biology↗

bioRxiv2024

Commonly used organoid culture media prevent ferroptosis

Organoids enable the recreation of organ physiology in vitro and serve as powerful models for biology in basic life science research and drug discovery and development. However, organoid culture requires complex media formulations that include antioxidants, potentially confounding experimental results sensitive to such conditions. Here we report that the growth conditions used commonly to generate organoid models inhibit ferroptosis, an iron-dependent form of lipid peroxidative cell death with relevance to human disease, thus rendering such models incompatible with ferroptosis research. We identify medium components that diminish or eliminate ferroptosis sensitivity and outline strategies for avoiding anti-ferroptotic culture conditions in organoid and other cell culture applications. These findings provide a roadmap for adapting organoid models for the study of ferroptosis and leveraging their strengths for advancing ferroptosis-modulating therapeutics.

cancer biology↗

bioRxiv2022

Biologically-informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post-treatment glioblastoma

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

cancer biology↗