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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

SWI/SNF remains localized to chromatin in the presence of SCHLAP1

SCHLAP1 is a long-noncoding RNA that is prognostic for progression to metastatic prostate cancer and promotes an invasive phenotype. SCHLAP1 is reported to function by depleting the core SWI/SNF subunit, SMARCB1, from the genome. SWI/SNF is a large, multi-subunit, chromatin remodeling complex that can be combinatorially assembled to yield hundreds to thousands of distinct complexes. Here, we investigated the hypothesis that SCHLAP1 affects only specific forms of SWI/SNF and that the remaining SWI/SNF complexes were important for the increased invasion in SCHLAP1 expressing prostate cells. Using several assays we found that SWI/SNF is not depleted from the genome by SCHLAP1 expression. We find that SCHLAP1 induces changes to chromatin openness but is not sufficient to drive changes in histone modifications. Additionally, we show that SWI/SNF binds many coding and non-coding RNAs. Together these results suggest that SCHLAP1 has roles independent of canonical SWI/SNF and that SWI/SNF broadly interacts with RNA.

cancer biology↗

bioRxiv2018

Classes of ITD predict outcomes in patients with AML treated with FLT3 inhibitors

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML). ITD mutations of Fms-like tyrosine kinase 3 (FLT3) receptor increase kinase activity, and are associated with poor prognostic outcomes. Currently, several small-molecule FLT3 inhibitors (FLT3i) are in clinical trials for targeted therapy of high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations in a patient might not guarantee effective clinical response to targeted inhibition of FLT3 kinase. Motivated by the heterogeneity of FLT3-ITD mutations, we sought to investigate the effects of FLT3-ITD structural features on response to treatment in AML patients. To this end, we developed HeatITup (HEAT diffusion for Internal Tandem dUPlication), an algorithm to efficiently and accurately identify ITDs and classify them based on their nucleotide composition into newly defined categories of \"typical\" or \"atypical\". Typical ITDs insert sequences are entirely endogenous to the FLT3 locus whereas atypical ITDs contain nucleotides exogenous to the wildtype FLT3. We applied HeatITup to our cohort of de novo and relapsed AML patients. Individuals with AML carrying typical ITDs benefited significantly more from FLT3i than patients with atypical ITDs, regardless of whether FLT3i was used after initial induction or at relapse. Furthermore, analysis of the TCGA AML cohort demonstrated improved survival for patients with typical ITDs treated with induction chemotherapy. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing towards personalized treatment for AML patients.

cancer biology↗

bioRxiv2018

The Repertoire of Mutational Signatures in Human Cancer

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

cancer biology↗

bioRxiv2018

Cryptsim: Modeling the evolutionary dynamics of the progression of Barrett’s esophagus to esophageal adenocarcinoma

To alleviate the over-diagnosis and overtreatment of premalignant conditions we need to predict their progression to cancer, and therefore, the dynamics of an evolutionary process. However, monitoring evolutionary processes in vivo is extremely challenging. Computer simulations constitute an attractive alternative, allowing us to study these dynamics based on a set of evolutionary parameters.\n\nWe introduce CryptSim, a simulator of crypt evolution inspired by Barretts esophagus. We detail the most relevant computational strategies it implements, and perform a simulation study showing that the interaction between neighboring crypts may play a crucial role in carcinogenesis.

cancer biology↗

bioRxiv2018

Radiopotentiation of Enzalutamide over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

While radiotherapy is the first line of treatment for prostate cancer, androgen blockade therapies are demonstrating significant survival benefit as monotherapies. As androgen blockade can cause cell death by apoptosis, it is likely that androgen blockade will potentiate the cytotoxic activities of radiotherapy. Here we tested the potential synergistic effects of these two treatments over two human metastatic prostate cancer cells by real time growth monitoring (RTCA), androgen-sensitive LNCaP cells and androgen-resistant PC-3. Both cell lines were highly resistant to high doses of radiotherapy. A pre-treatment of LNCaP cells with IC50 concentrations of enzalutamide significantly sensitized them to radiotherapy through enhanced apoptosis. In contrast, enzalutamide resistant PC-3 cells were not sensitized to radiotherapy by androgen blockade. These results provide evidence that the enzalutamide/radiotherapy combination could maximize therapeutic responses in patients with enzalutamide-sensitive prostate cancer.

cancer biology↗

bioRxiv2018

Pleotropic effects of PPARD accelerate colorectal tumor progression and invasion

Colorectal carcinogenesis (CRC) progression requires additional molecular mechanisms to APC mutations/aberrant {beta}-catenin signaling. PPARD is a druggable ligand-activated nuclear receptor that regulates essential genes involved in cell fate. PPARD is upregulated in intestinal epithelial cells (IECs) of human colorectal adenomas and adenocarcinomas. The mechanistic significance of PPARD upregulation in CRC remains unknown. Here we show that targeted PPARD overexpression in IECs of mice strongly augmented {beta}-catenin activation via BMP7/TAK1 signaling, promoted intestinal tumorigenesis in Apcmin mice, and accelerated CRC progression and invasiveness in mice with IEC-targeted Apc{Delta}580 mutation. Human CRC invasive fronts had higher PPARD expression than their paired adenomas. A PPARD agonist (GW501516) enhanced APC{Delta}580 mutation-driven CRC, while a PPARD antagonist (GSK3787) suppressed it. Functional proteomics analyses and subsequent validation studies uncovered PPARD upregulation of multiple pro-invasive pathways that drive CRC progression (e.g. PDGFR{beta}, AKT1, CDK1 and EIF4G1). Our results identify novel mechanisms by which PPARD promotes CRC invasiveness and provide the rational for the development of PPARD antagonists to suppress CRC.

cancer biology↗

bioRxiv2018

On the design of treatment schedules that avoid chemotherapeutic resistance

We introduce a method of designing treatment schedules for a model three-component replicator dynamical system that avoids chemotherapeutic resistance by controlling and managing the competitive release of resistant cells in the tumor. We use an evolutionary game theory model with prisoners dilemma payoff matrix that governs the competition among healthy cells, chemo-sensitive cells, and chemo-resistant cells and the goal is to control the evolution of chemo-resistance via the competitive release mechanism. The method is based on nonlinear trajectory design and energy transfer methods first introduced in the orbital mechanics literature for Hamiltonian systems. By using the structure of the trajectories defined by solutions of the replicator system for different constant chemotherapeutic concentrations (which produces a curvilinear coordinate system spanning the full region), we construct periodic (closed) orbits by switching the chemo-dose at carefully chosen times and appropriate levels to design schedules that are superior to both maximum tolerated dose (MTD) schedules and low-dose metronomic (LDM) schedules, both of which ultimately lead to fixation of either sensitive cells or resistant cells. By keeping the three sub-populations of cells in competition with each other, neither the sensitive cell population nor the resitant cell population are able to dominate as we balance the populations indefinitely (closed periodic orbits), thereby avoiding fixation of the cancer cell population and re-growth of a resistant tumor. The schedules we design have the feature that they maintain a higher average population fitness than either the MTD or the LDM schedules.\n\nPACS numbers: 87.23.Kg; 87.55.de; 87.19.Xj; 87.19.lr

cancer biology↗

bioRxiv2018

In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

PurposeMost breast cancers (BCs) express estrogen receptor (ER) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ER intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ER content in BC cells.\n\nMethodsWe screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nResultsMitoxantrone and thioridazine induced ER downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ER content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nConclusionsWe suggest that the modulation of the ER intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for thioridazine in primary and metastatic ET-resistant BC treatment.

cancer biology↗

bioRxiv2018

The UCSC Xena Platform for cancer genomics data visualization and interpretation

UCSC Xena is a visual exploration resource for both public and private omics data, supported through the web-based Xena Browser and multiple turn-key Xena Hubs. This unique archecture allows researchers to view their own data securely, using private Xena Hubs, simultaneously visualizing large public cancer genomics datasets, including TCGA and the GDC. Data integration occurs only within the Xena Browser, keeping private data private. Xena supports virtually any functional genomics data, including SNVs, INDELs, large structural variants, CNV, expression, DNA methylation, ATAC-seq signals, and phenotypic annotations. Browser features include the Visual Spreadsheet, survival analyses, powerful filtering and subgrouping, statistical analyses, genomic signatures, and bookmarks. Xena differentiates itself from other genomics tools, including its predecessor, the UCSC Cancer Genomics Browser, by its ability to easily and securely view public and private data, its high performance, its broad data type support, and many unique features.

cancer biology↗

bioRxiv2018

Low frequency ultrasound enhances chemotherapy sensitivity and induces autophagy in human paclitaxel resistance prostate cancer PC-3R cells through the ERs-mediated PI3K/Akt/mTOR signaling pathway

Sonodynamic therapy (SDT) as an emerging tumor-assisting method has attracted a great deal of interest in tumor therapy research in recent years. However, autophagy has been observed in several cancer cells treated with SDT and its role and mechanism are not clear. In the present study, we have investigated the effect of low frequency ultrasound on paclitaxel(PTX) resistance prostate cancer PC-3R cells and demonstrated that low frequency ultrasound could induce cancer cell apoptosis, inhibit the expression of multiple drug resistance genes (MRP3, MRP7 and P-glycoprotein) and reverse drug resistance; we further found that low frequency ultrasound induced autophagy in PC-3R cells. Our results demonstrated that low frequency ultrasound enhanced chemotherapy sensitivity and induced autophagy in PC-3R cells by inhibiting the PI3K/AKT/mTOR pathway. Moreover, we observed that low frequency ultrasound-induced cell autophagy was correlated with endoplasmic reticulum stress (ERs). 4-phenylbutyric acid (4-PBA) - mediated protection against ERs clearly implicated ERs in the activation of autophagy and cell apoptosis. In addition, the results showed that ERs served as an upstream effector of the PI3K/AKT/mTOR pathway. More importantly, we observed that inhibition of low frequency ultrasound-induced autophagy enhanced ERs and improved the role of low frequency ultrasound in reversing drug resistance. Over all, our findings provide new insights into the molecular mechanisms underlying low frequency ultrasound-mediated reversal of drug resistance and autophagy in PC-3R cells and support autophagy as a potential agent for enhancing anti-cancer effect of SDT.

cancer biology↗

bioRxiv2018

Oncogenic Wnt/STOP signaling regulates ribosome biogenesis in vivo

Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a PORCN inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The analysis of temporal changes following Wnt withdrawal demonstrated direct and indirect regulation of >3,500 Wnt activated genes (23% of the transcriptome). Regulation was both transcriptional via Wnt/{beta}-catenin, and through the modulation of protein abundance of important transcription factors including MYC via Wnt/STOP. Our study identifies a central role of Wnt /{beta}-catenin and Wnt/STOP signaling in controlling ribosomal biogenesis, a key driver of cancer proliferation.

cancer biology↗

bioRxiv2018

Novel Molecular Classification of Muscle-Invasive Bladder Cancer Opens New Treatment Opportunities

BackgroundMuscle-invasive bladder tumors are associated with high risk of relapse and metastasis even after neoadjuvant chemotherapy and radical cystectomy. Therefore, further therapeutic options are needed and molecular characterization of the disease may help to identify new targets.\n\nObjectiveThe aim of this work is to characterize muscle-invasive bladder tumors at molecular levels using computational analyses.\n\nDesign, Settings and ParticipantsThe TCGA cohort of muscle-invasive bladder cancer patients was used to describe these tumors.\n\nOutcome Measurements and Statistical AnalysisProbabilistic graphical models, layer analyses based on sparse k-means coupled with Consensus Cluster, and Flux Balance Analysis were applied to characterize muscle-invasive bladder tumors at functional level.\n\nResultsLuminal and Basal groups were identified, and an immune molecular layer with independent value was also described. Luminal tumors had decreased activity in the nodes of epidermis development and extracellular matrix, and increased activity in the node of steroid metabolism leading to a higher expression of androgen receptor.\n\nThis fact points to androgen receptor as a therapeutic target in this group. Basal tumors were highly proliferative according to Flux Balance Analysis, which make these tumors good candidates for neoadjuvant chemotherapy. Immune-high group had higher expression of immune biomarkers, suggesting that this group may benefit from immune therapy.\n\nConclusionsOur approach, based on layer analyses, established a Luminal group candidate for androgen receptor inhibitor therapy, a proliferative Basal group which seems to be a good candidate for chemotherapy, and an immune-high group candidate for immunotherapy.\n\nPatient SummaryMuscle-invasive bladder cancer has a poor prognosis in spite of appropriate therapy. Therefore, it is still necessary to characterize these tumors to propose new therapeutic targets. In this work we used computational analyses to characterize these tumors and propose treatments.

cancer biology↗

bioRxiv2018

MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ Breast Cancer

MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of miR196a are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein. Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long range transcriptional regulation between promoter and enhancer elements bound by ER. Expression of this miRNA is significantly increased in models of hormone receptor positive disease resistance. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease. This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.

cancer biology↗

bioRxiv2018

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization

Glioblastoma (GBM) is a lethal brain cancer known for its potent immunosuppressive effects. Loss of Methylthioadenosine Phosphorylase (MTAP) expression, via gene deletion or epigenetic silencing, is one of the most common alterations in GBM. Here, we show that MTAP loss in GBM cells is correlated with differential expression of immune regulatory genes. In silico analysis of gene expression profiles in GBM samples revealed that low MTAP expression is correlated with reduced proportions of {gamma}{delta}T cells, fewer activated CD4 cells, and an increased proportion of M2 macrophages. Using in vitro macrophage models, we found that methylthioadenosine (MTA), the metabolite that accumulates as a result of MTAP loss in GBM cells, promotes the immunosuppressive alternative activation (M2) of macrophages. We show that this effect of MTA on macrophages is independent of IL4/IL3 signaling, is mediated by the adenosine A2B receptor, and can be pharmacologically reversed. This study suggests that MTAP loss in GBM cells contributes to the immunosuppressive microenvironment, and that MTAP status should be a factor for consideration in understanding GBM immune states and devising immunotherapy-based approaches for treating MTAP-null GBM.

cancer biology↗

bioRxiv2018

Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-{kappa}B pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.\n\nIMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-{kappa}B signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

cancer biology↗

bioRxiv2018

Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

Drug resistance to Osimertinib, a 3rd-generation EGFR-TKI is inevitable. Autophagy plays a contradictory role in resistance of 1st and 2nd generation EGFR-TKI, and its significance in osimertinib resistance is much less clear. We therefore investigated whether autophagy determines osimertinib resistance. First, osimertinib induced autophagy to a much greater extent than that of gefitinib, and autophagy inhibition further increased osimertinib efficacy. Next, enhanced autophagy was found in osimertinib resistant cells and autophagy inhibition partially reversed osimertinib resistance. Enhanced stem-cell like properties were found in resistant cells, and siRNA-knock down of SOX2 or ALDH1A1reversed osimertinib resistance. Of note, autophagy inhibition or siRNA-knock down of Beclin-1 decreased expression of SOX2 and ALDH1A1 and stem-cell like properties. Next, autophagy inhibition and osimertinib in combination effectively blocked tumor growth in xenografts, which was associated with decreased autophagy and stem cell-like properties in vivo. Finally, enhanced autophagy was found in lung cancer patients with resistance to osimertinib. In conclusion, the current study delineates a previously unknown function of autophagy in determining osimertinib resistance through promoting stem-cell like properties.

cancer biology↗

bioRxiv2018

Patterns of tumor progression predict small and tissue-specific tumor-originating niches

Cancer development is a multistep process in which cells increase in malignancy through progressive alterations. The early phase of this process is hardly observable which aggravates an understanding of later tumor development. We shed light on this initial phase with a cell-based stochastic model calibrated with epidemiological data from the tissue scale. Our model allows to estimate the number of tumor cells needed for tumor formation in human tissues based on data on the diagnosed ratios of benign and malignant tumors. We find that the minimal number of cells needed for tumor formation is surprisingly small and largely depends on the tissue type. Our results point towards the existence of tumor-originating niches in which the fate of tumor development is early decided. Our estimate for the human colon agrees well with the size of the stem cell niche in colonic crypts. Our estimates might help to identify the tumor-originating cell type, e.g. our analysis suggests for glioblastoma that the tumors originate from a cell type competing in a range of 300 - 1900 cells.\n\nSummaryWe estimate the number of tumor cells needed for tumor formation in human tissues and propose the existence of small and tissue-specific tumor-originating niches which might help to find tumor-originating cell types, in particular in glioblastoma.

cancer biology↗

bioRxiv2018

NetrinG1/NGL-1 Axis promotes pancreatictumorigenesis through cancer associated fibroblastderived nutritional supply and immunosuppression

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. NetG1+ cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These pro-tumor functions were controlled by a signaling circuit downstream to NetG1, which was comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally blocking NetG1 with a neutralizing antibody stunted in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SignificancePDAC is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of CAFs and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. A better understanding of the role of CAFs in PDAC may lead to the identification of new targets for therapeutic intervention. Here, we uncovered roles for NetG1 in CAFs to promote tumorigenesis. NetG1 was important for two major CAF functions: the metabolic support of PDAC cells and the intrinsic immunosuppressive capacity of CAFs. Our results helped clarify the role that CAFs play in PDAC, by defining CAF phenotypes through NetG1 expression. Moreover, we established a link between CAF driven metabolism and their intrinsic immunosuppressive capacity, and identified a signaling circuit that governs NetG1 functions. Finally, we demonstrated the therapeutic potential of inhibiting NetG1 in vivo by limiting tumorigenesis in mice with a neutralizing antibody, illustrating that targeting stromal NetG1 could be an attractive therapeutic approach.

cancer biology↗