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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 163 records · Page 9Linked to original sources

bioRxiv2019

Exponential Growth of Glioblastoma In Vivo Driven by Rapidly Dividing and Outwardly Migrating Cancer Stem Cells

How overall tumor growth emerges from the properties of functionally heterogeneous tumor cell subpopulations is a fundamental question of cancer biology. Here we combined lineage tracing, continuous monitoring of tumor mass, proliferation assays and transcriptomics with mathematical modeling and statistical inference to dissect the growth of glioblastoma in mice. We found that tumors grow exponentially at the rate of symmetric divisions of brain tumor stem cells (BTSCs). Spatial modeling predicts, and data show, that BTSCs accumulate at the tumor rim rather than in the core. The physiological differentiation hierarchy downstream of BTSCs is preserved in mice and humans: transit amplifying progenitors give rise to terminally differentiated cells. Consistent with our quantification of the mechanisms underlying tumor growth, molecular data show elevated expression of cell cycle-and migration-related genes in BTSCs. Our systematic approach reveals fundamental properties of glioblastoma and may be transferable to the study of other animal models of cancer.

cancer biology↗

bioRxiv2022

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway.

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials. Once sentence summaryPD-L1 promotes oncolytic virus efficacy.

cancer biology↗

bioRxiv2019

Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics

Covalent inhibitors of the KRASG12C oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRASG12C inhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive KRASi proteome website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.

cancer biology↗

bioRxiv2026

Transcriptomic profiling of mouse mammary tumors enables prognostic and predictive biomarker discovery for human breast cancers

The development and validation of prognostic and predictive biomarkers in breast cancer is limited by the availability of well-annotated datasets linking tumor molecular features to treatment response and survival outcomes. To address this need, we generated an extensive mouse models dataset comprised of 26 immunocompetent mammary tumor models spanning diverse genetic backgrounds, epithelial-mesenchymal states, the basal-luminal axis, and distinct immune microenvironments. For each model, we measured survival under no treatment, immune checkpoint inhibition (ICI), and carboplatin/paclitaxel chemotherapy. We performed RNA-seq on baseline tumors and on 7-day on-treatment samples for both regimens. Using baseline murine tumor gene expression features, we trained a machine learning Elastic Net model that predicted survival outcomes on multiple human breast cancer datasets with performance comparable to that of existing prognostic assays. We next trained models for ICI benefit, using either the untreated or 7-day ICI treated samples; both models predicted ICI benefit on human ICI treated datasets, with the 7-day treated tumor model showing better performance. We also developed a predictor of carboplatin/paclitaxel response that performed well in mice but did not generalize to human chemotherapy cohorts. Finally, we compared multiple computational approaches, including XGBoost, random forests, and support vector regression; all methods successfully predicted survival outcomes, with Elastic Net offering the best performance and interpretability. These results indicate conserved cancer biology between mouse and human tumors for prognosis and ICI response and establish this large preclinical dataset with linked phenotypic and genomic data, as a resource for benchmarking computational methods for survival prediction. SignificanceThe development of a genomically and phenotypically diverse murine tumor dataset with linked treatment outcomes establishes a robust translational resource to develop, test, and benchmark clinically relevant prognostic and therapeutic response biomarkers.

cancer biology↗

bioRxiv2023

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

cancer biology↗

bioRxiv2026

Small-RNA Profiling Links 5'-tRNA Halves to Post-therapeutic Disease Persistence and Poor Patient Survival in Glioblastoma

Glioblastoma (GBM) is a highly lethal brain cancer with limited therapeutic durability, where the majority of patients develop recurrent or persistent disease after standard chemoradiotherapy. Meanwhile, tRNA-derived fragments (tRFs) have become increasingly relevant to cancer biology; however, their clinical relevance in GBM remains undefined. Here, we report that a specific family of tRFs, 5-tRNA halves (tiR5s) dominates the small RNA landscape of GBM patient tumors and associates with worse overall survival, post-therapeutic disease persistence, and pro-invasive proteogenomic pathways across two independent GBM patient cohorts. This association between elevated tiR5 levels and therapeutic resistance re-emerges in radiation-resistant GBM xenograft models. Our findings reveal that tiR5s are an underappreciated molecular feature of highly aggressive GBM tumors, supporting further investigation into their biological roles and prognostic utility in GBM. HighlightsO_LItiR5s are the predominant tRF family in primary GBM patient tumors C_LIO_LIElevated tiR5 expression distinguishes primary GBM tumors that develop persistent disease after first-line therapy C_LIO_LIRadiation-resistant GBM PDX models show elevated tiR5 expression C_LIO_LIElevated tiR5 expression associates with poor overall patient survival and pro-invasive molecular programs in GBM patient tumors C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/738483v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@3219d5org.highwire.dtl.DTLVardef@13e09b8org.highwire.dtl.DTLVardef@1f0328borg.highwire.dtl.DTLVardef@867b09_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial mesenchymal transition

The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of {delta}-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

cancer biology↗

bioRxiv2025

Survivin as a Multifaceted Oncogenic Driver and Therapeutic Target in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a heterogeneous malignancy in which clear cell RCC (ccRCC) represents the most aggressive subtype. Survivin (BIRC5), an inhibitor of apoptosis and key regulator of mitosis, is frequently overexpressed in RCC and associated with poor prognosis, yet its broader role in kidney cancer biology remains poorly defined. Here, we analyzed transcriptomic data from the TCGA-KIRC cohort and found that advanced-stage ccRCC exhibits widespread dysregulation of cell cycle pathways, with 1,484 genes upregulated and 479 genes downregulated in stage IV compared to stage I tumors. To define survivins functional contribution, we performed loss-of-function and pharmacologic inhibition studies in RENCA cells. Survivin knockdown or treatment with the small molecule inhibitor YM155 significantly reduced proliferation, S-phase entry, and Cyclin D1 expression, while also impairing both collective and single-cell migration. Beyond cell cycle control, survivin depletion induced notable changes in mitochondrial morphology and bioenergetics, including increased mitochondrial content coupled with reduced oxygen consumption, suggesting accumulation of dysfunctional mitochondria due to impaired clearance. Collectively, these findings identify survivin as a multifaceted oncogenic driver in RCC that integrates cell cycle progression, cytoskeletal organization, and mitochondrial homeostasis. By revealing survivins dual roles in proliferative and metabolic adaptation, this work highlights survivin as both a prognostic biomarker and a therapeutic vulnerability, supporting future strategies that combine survivin inhibition with metabolic or cell cycle-directed therapies for advanced kidney cancer.

cancer biology↗

bioRxiv2020

A Drosophila model of oral peptide therapeutics for adult intestinal stem cell tumors

The proto-oncogene YAP /Yki, a transcription co-factor of the Hippo pathway, has been linked to many cancers. YAP interacts with DNA-binding TEAD/Sd proteins to regulate expression of its transcriptional targets. Disruption of YAP-TEAD therefore offers a potential therapeutic strategy. The mammalian Vestigial Like (VGLL) protein, specifically its TONDU domain, has been shown to competitively inhibit YAP-TEAD interaction and a TONDU peptide can suppress YAP-induced cancer. As TONDU could potentially be developed into a therapeutic peptide for multiple cancers, we evaluated its efficacy in Yki-driven adult Intestinal Stem Cell (ISC) tumors in Drosophila. We show that oral uptake of the TONDU peptide is highly effective at inhibiting Yki-driven gut tumors by suppressing YAP-TEAD interaction. Comparative proteomics of early and late stage Yki-driven ISC tumors revealed enrichment of a number of proteins, including members of the integrin signaling pathway, such as Talin, Vinculin and Paxillin. These, in turn displayed a decrease in their levels in TONDU-peptide treated tumors. Further, we show that Sd binds to the regulatory region of integrin-coding gene, mew, which codes for PS1, a key integrin of the ISCs. In support to a possible role of integrins in Yki-driven ISC tumors, we show that genetic downregulation of mew arrests Yki-driven ISC proliferation, reminiscent of the effects of TONDU peptide. Altogether, our findings present a novel platform for screening therapeutic peptides and provide insights into tumor suppression mechanisms. SIGNIFICANCE STATEMENTDiscovering novel strategies to inhibit oncogene activity is a priority in cancer biology. As signaling pathways are widely conserved between mammals and Drosophila, these questions can be effectively addressed in this model organism. Here, we show that progression of Drosophila Intestinal Stem Cell (ISC) tumors induced by gain of an oncogenic form of the transcription co-factor Yki can be suppressed by feeding a peptide corresponding to the conserved TONDU domain of Vestigial (Vg), which blocks binding of Yki to the Sd transcription factor. Further, we show that down regulation of the integrin signaling pathway is causally linked to TONDU-peptide-mediated ISC tumor suppression. Our findings reveal that Drosophila can be successfully used to screen peptides for their therapeutic applications.

cancer biology↗

bioRxiv2021

XePhIR: The zebrafish Xenograft Phenotype Interactive Repository

Zebrafish xenografts are an established model in cancer biology, with a steadily rising number of models and users. However, as of yet, there is no platform dedicated to standardizing protocols and sharing data regarding zebrafish xenograft phenotypes. Here, we present the Xenograft Phenotype Interactive Repository (XePhIR, www.xephir.org) as an independent data sharing platform to deposit, share and repurpose zebrafish xenograft data. Deposition of data and publication with XePhIR will be done after the acceptation of the original publication. This will enhance the reach of the original research article, enhance visibility, and does not interfere with publication or copyrights of the original article. With XePhIR, we strive to fulfill these objectives and reason that this resource will enhance reproducibility and showcase the appeal and applicability of the zebrafish xenograft model.

cancer biology↗

bioRxiv2025

Transcriptomic splicing analysis reveals a gene-independent form of TE reactivation in tumors representing unrecognized source of oncogenes and neoantigens

Transposable elements (TEs) are reactivated in tumors and serve as significant contributors to tumor transcriptomic complexity and heterogeneity. However, their repetitive nature and diverse transcriptional forms have hindered efforts to characterize TE-derived transcripts independent of host gene contexts. Here, using our self-developed splicing-junction analysis tool ASJA, we systematically interrogated TE transcription across 32 cancer types, identifying transcripts autonomously initiated from and exclusively spliced among TEs with high TE content, termed TEtrans. Our analysis revealed 5,361 TEtrans exhibiting pan-cancer prevalence, tumor-specific expression and features of mature transcripts, including canonical splicing, 5 caps and polyA tails. Mostly unannotated and enriched in intergenic regions, TEtrans are predominantly derived from primate-specific classes with conserved splice pattern. TEtrans burden demonstrates heterogeneous associations with prognosis and immune activity across cancers, while their expression can be epigenetically dual-regulated by stemness- and inflammation-associated transcription factors. Functional studies uncovered that TEtrans could act as oncogenes, exemplified by tsTE1, a HERVH-derived transcript that promotes colorectal cancer proliferation by enhancing TOP1-mediated DNA supercoil relaxation. Remarkably, [~]7.2% of TEtrans are identified to encode tumor neoantigens, including viral proteins and unannotated peptides, which are shared among patients and validated by proteogenomic analysis. These TEtrans-derived neoantigens are immunogenic both in vitro and in vivo, and exceed neoepitopes from genomic alterations in abundance per tumor, particularly in cancers with low mutational burden. Collectively, as a gene-independent form of TE-derived transcripts, TEtrans represents a unique source of oncogenes and tumor neoantigens, expanding the functional repertoire of TEs in cancer biology and offering new avenues for therapeutic targeting. HighlightsO_LITEtrans are tumor-specific transcripts with conserved splicing patterns, predominantly derived from primate TEs in intergenic regions. C_LIO_LITEtrans expression is epigenetically activated and dually regulated by stemness/inflammation transcription factors. C_LIO_LITEtrans function as oncogenes, exemplified by tsTE1 enhancing TOP1-mediated DNA relaxation. C_LIO_LITEtrans encode tumor neoantigens that elicit CD8+ T cell responses, providing targets for immunotherapy, especially in low-mutation tumors. C_LI Abstract figure O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/640928v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@1d2d4cforg.highwire.dtl.DTLVardef@918f14org.highwire.dtl.DTLVardef@489465org.highwire.dtl.DTLVardef@1069d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreaticduct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

cancer biology↗

bioRxiv2025

NSUN2 drives intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signalling

Colorectal cancer is initiated by loss of the APC gene, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5+ ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post-transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m5C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is upregulated in multiple CRC mouse models and human tumours and its depletion impairs ISC expansion and hyperproliferation, leading to reduced tumour initiation. Transcriptome-wide bisulphite sequencing revealed that NSUN2-mediates m5C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc-deficient models and oncogenic KrasG12Dexpression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes NSUN2 as a key regulator of ISC-driven CRC initiation and describes a novel molecular mechanism linking m5C methylation to MAPK driven stem cell transformation.

cancer biology↗

bioRxiv2026

A multitask single-cell analysis framework with knowledge graph as a prior

Single-cell RNA sequencing has reshaped cancer biology by revealing the cellular and molecular diversity of the tumor microenvironment, yet most analysis pipelines still treat clustering, annotation, pathway scoring, metabolic inference, and cell-cell communication as separate tasks. Here, we present scKNIFE (Knowledge graph-based NMF for Inference of Functional Entities), a unified graph-regularized non-negative matrix factorization framework that jointly reconstructs single-cell expression profiles and infers activities of diverse biological entities, including pathways, cell-type markers, metabolic reactions and tasks, ligand-receptor interactions, and cell-state programs. By embedding a heterogeneous knowledge graph directly into the factorization objective, scKNIFE propagates information between biologically related entities through Laplacian regularization while sparsity constraints preserve interpretability. The integrated prior graph spans 47,274 nodes and 506,620 edges, assembled from complementary resources including Gene Ontology, Reactome, Hallmark gene sets, Human-GEM, CellChat, PanglaoDB, Cytopus, and Tabula Muris-derived annotations. Across multiple cancer-focused single-cell datasets, scKNIFE yields competitive to leading performance for clustering and cell-type annotation, while also recovering biologically coherent metabolic programs that agree with dedicated metabolism-focused methods and capture therapy-response-associated states. In addition, the framework supports downstream inference of cell-type-specific biological activities from a single latent representation. Together, these results establish scKNIFE as a modular and extensible framework for end-to-end biological interpretation of single-cell cancer transcriptomics

cancer biology↗

bioRxiv2019

DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. Up to now there is only one identified molecular target responsible for driving the disease, the chimeric protein encoded by DNAJB1-PRKACA (J-PKAca). Immune cells have been identified as key players in liver cancer biology, however the effect of J-PKAca on inflammation in the liver microenvironment is not known. Here we report a new zebrafish model of FLC with non-invasive live imaging capabilities that allows the study of the interactions between immune cells and transformed hepatocytes. We found that overexpression of the dnajb1a-prkcaaa fusion gene specifically in hepatocytes induces early malignancy features in FLC transgenic larvae, such as increased liver and hepatocyte size. In addition, this aberrant form of PKA promotes a pro-inflammatory liver microenvironment by increasing the number of neutrophils and macrophages in the liver area and inducing macrophage polarization to a pro-inflammatory phenotype. Increased caspase-a activity was also found in the liver of FLC transgenic larvae. Importantly, pharmacological inhibition of TNF secretion and caspase-a activity decreased liver size and inflammation. Overall, these findings suggest that inflammation may be an early feature of FLC involved in progression, and that targeting TNFand caspase-1 may be beneficial in treating FLC.

cancer biology↗

bioRxiv2022

Approaches to generating virtual patient cohorts with applications in oncology

Virtual clinical trials (VCTs) have gained popularity for their ability to rationalize the drug development process using mathematical and computational modelling, and to provide key insights into the mechanisms regulating patient responses to treatment. In this chapter, we cover approaches for generating virtual cohorts with applications in cancer biology and treatment. VCTs are an effective tool for predicting clinical responses to novel therapeutics and establishing effective treatment strategies. These VCTs allow us to capture inter-individual variability (IIV) which can lead to diversity in patient drug responses. Here we discuss three main methodologies for capturing IIV with a VCT. First, we highlight the use of population pharmacokinetic (PopPK) models, which extrapolate from empirical data population PK parameters that best fits the individual variability seen in drug disposition using non-linear mixed effects models. Next, we show how virtual patients may be sampled from a normal distribution with mean and standard deviation informed from experimental data to estimate parameters in a mechanistic model that regulates drug PKs. Lastly, we show how optimization techniques can be used to calibrate virtual patient parameter values and generate the VCT. Throughout, we compare and contrast these methods to provide a broader view of the generation of virtual patients, and to aid the decision-making process for those looking to leverage virtual clinical trials in their research.

cancer biology↗

bioRxiv2020

Fishing for contact: Modeling perivascular glioma invasion in the zebrafish brain.

Glioblastoma multiforme (GBM) is a highly invasive, central nervous system (CNS) cancer for which there is no a cure. Invading tumor cells evade treatment, limiting the efficacy of the current standard of care regimen. Understanding the underlying invasive behaviors that support tumor growth may allow for generation of novel GBM therapies. Zebrafish (Danio rerio) are attractive for genetics and live imaging, and have in recent years, emerged as a model system suitable for cancer biology research. While other groups have studied CNS tumors using zebrafish, few have concentrated on the invasive behaviors supporting the development of these diseases. Previous studies demonstrated that one of the main mechanisms of GBM invasion is perivascular invasion, i.e. single tumor cell migration along blood vessels. Here, we characterize phenotypes, methodology, and potential therapeutic avenues for utilizing zebrafish to model perivascular GBM invasion. Using patient derived xenolines or an adherent cell line, we demonstrate tumor expansion within the zebrafish brain. Within 24 hours post-intracranial injection, D54-MG-tdTomato glioma cells produce finger-like projections along the zebrafish brain vasculature. As few as 25 GBM cells were sufficient to promote single cell vessel co-option. Of note, these tumor-vessel interactions are CNS specific, and do not occur on pre-existing blood vessels when injected into the animals peripheral tissue. Tumor-vessel interactions increase over time and can be pharmacologically disrupted through inhibition of Wnt signaling. Therefore, zebrafish serve as a favorable model system to study perivascular glioma invasion, one of the deadly characteristics that make GBM so difficult to treat.

cancer biology↗

bioRxiv2024

Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma maintenance

Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma maintenance, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that -2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding -2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon -2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that -2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.

cancer biology↗