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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 67,351 bioRxiv papers from 296,699 authors.

Most downloaded bioRxiv papers, since beginning of last month

in category cancer biology

2,212 results found. For more information, click each entry to expand.

2121: Quantitative Assessment of Colorectal Cancer Progression: a Comparative Study of Linear and Nonlinear Microscopy Techniques
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Posted to bioRxiv 23 Aug 2018

Quantitative Assessment of Colorectal Cancer Progression: a Comparative Study of Linear and Nonlinear Microscopy Techniques
4 downloads cancer biology

J. Adur, L. Erbes, M. Bianchi, S. Ruff, A. Zeitoune, M.F. Izaguirre, C.L. Cesar, H.F. Carvahlo, V.H. Casco

BACKGROUND AND AIMS: Colorectal cancer (CRC) is a disease that can be prevented if is diagnosed and treated at pre-invasive stages. Thus, the monitoring of colonic cancer progression can improve the early diagnosis and detection of malignant lesions in the colon. This monitoring should be performed with appropriate image techniques and be accompanied by proper quantification to minimize subjectivity. We have monitored the mice CRC progression by image deconvolution, two-photon emission fluorescence (TPEF) and second harmonic generation (SHG) microscopies and present different quantization indices for diagnosis. METHODS: The Azoxymethane (AOM) / dextran sodium sulfate (DSS) protocol was used. 35 eight-week old male BALB/cCmedc mice were used and distal colon segments were dissected at day zero and fourth, eighth, sixteen, and twenty weeks after injection. These segments were observed with linear and nonlinear optical microscopies and several parameters were used for quantification. RESULTS: Crypt diameter higher than 0.08 mm and increased fluorescence signal intensity in linear images; as well as aspect relation above 0.7 and altered organization reflexed by high-energy values obtained from SHG images, away from those obtained in normal tissues. CONCLUSION: the combination of linear and nonlinear signals improve the detection and classification of pathological changes in crypt morphology/distribution and collagen fiber structure/arrangement. In combination with standard screening approaches for CRC, the proposed methods improve the detection of the disease in its early stages, thereby increasing the chances of successful treatment.

2122: PRR14 Overexpression Promotes Cell Growth, Epithelial to Mesenchymal Transition and Metastasis of Colon Cancer via the AKT Pathway
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Posted to bioRxiv 12 Jun 2019

PRR14 Overexpression Promotes Cell Growth, Epithelial to Mesenchymal Transition and Metastasis of Colon Cancer via the AKT Pathway
4 downloads cancer biology

Fangfang Li, Chundong Zhang, Lijuan Fu

Background PRR14 (Proline rich protein 14) was firstly identified for its ability to specify and localize heterochromatin during cell cycle progression. Aberrant expression of PRR14 is associated with the tumorigenesis and progression of lung cancer. However, its involvement in colon cancer remains unknown. Herein, we report the role of PRR14 in colon cancer. Methods Colon cancer tissue microarray was used to analyze and compare the expression of PRR14 among some clinicopathological characteristics of colon cancer. HCT116 and RKO cells were transfected with siRNA to downregulate PRR14 expression. The roles of PRR14 in proliferation, migration and invasion of the cell lines were determined using cell counting kit-8, colony formation assay, wound healing assay and transwell assays respectively. The expression of PRR14 was measured by using immunofluorescence, qRT- PCR and western blot. Results PRR14 was highly expressed in colon cancer tissues, and the expression level was correlated with tumor size, distant metastasis and Tumor Node Metastasis stages. Functional study revealed that downregulation of PRR14 inhibited colon cancer cells growth, migration and invasion. Furthermore, knockdown of PRR14 inhibited epithelial-mesenchymal transition (EMT) process, cell cycle-associated proteins expression and p-AKT level. Conclusion PRR14 may promote the progression and metastasis of colon cancer, and may be a novel prognostic and therapeutic marker for the disease.

2123: Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells
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Posted to bioRxiv 28 Jun 2018

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells
4 downloads cancer biology

Alicja Sznarkowska, Anna Kostecka, Anna Kawiak, Pilar Acedo, Mattia Lion, Alberto Inga, Joanna Zawacka-Pankau

The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene. By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA) applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch. Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.

2124: Genetic Load Makes Cancer Cells More Sensitive To Common Drugs: Evidence From Cancer Cell Line Encyclopedia
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Posted to bioRxiv 17 May 2017

Genetic Load Makes Cancer Cells More Sensitive To Common Drugs: Evidence From Cancer Cell Line Encyclopedia
4 downloads cancer biology

Ana B. Pavel, Kirill S Korolev

Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong, with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.

2125: Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.
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Posted to bioRxiv 23 Jul 2017

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.
4 downloads cancer biology

Lucy Ireland, Almudena Santos, Fiona Campbell, Carlos Figueiredo, Lesley Ellies, Ulrike Weyer-Czernilofsky, Thomas Bogenrieder, Michael Schmid, Ainhoa Mielgo

Breast cancer remains the leading cause of cancer death in women due to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumours. 75% of breast cancer patients show activation of Insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in a pre-clinical breast cancer model compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

2126: Inferring rates of metastatic dissemination using stochastic network models
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Posted to bioRxiv 20 Jun 2018

Inferring rates of metastatic dissemination using stochastic network models
4 downloads cancer biology

Philip Gerlee, Mia Johansson

The formation of metastases is driven by the ability of cancer cells to disseminate from the site of the primary tumour to target organs. The process of dissemination is constrained by anatomical features such as the flow of blood and lymph in the circulatory system. We exploit this fact in a stochastic network model of metastasis formation, in which only anatomically feasible routes of dissemination are considered. By fitting this model to two different clinical datasets (tongue & ovarian cancer) we show that incidence data can be modelled using a small number of biologically meaningful parameters. The fitted models reveal site specific relative rates of dissemination and also allow for patient-specific predictions of metastatic involvement based on primary tumour location and stage. Applied to other data sets this type of model could yield insight about seed-soil effects, and could also be used in a clinical setting to provide personalised predictions about the extent of metastatic spread.

2127: Cell Dynamics in the Wound Healing Process in Tumor Environment After Treatments
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Posted to bioRxiv 14 Oct 2016

Cell Dynamics in the Wound Healing Process in Tumor Environment After Treatments
4 downloads cancer biology

Leili Shahriyari

Although the failure of cancers treatments has been mostly linked with the existence of resistant cells or cancer stem cells, new findings show a significant correlation between circulating inflammatory biomarkers and treatment failures. Most cancer treatments cause necrotic cell deaths in the tumor environment. Necrotic cells send signals to the immune cells to start the wound healing process in the tissue. Therefore, we assume after stopping treatments there is a wound that needs to be healed. The stochastic simulations of epithelial cell dynamics after a treatment, which only kills cells without changing the tumor's inflammatory environment, show that higher fitness of cancer cells causes earlier relapses. Moreover, the tumor returns even if a single cancer cell with high fitness remains in the wound's boundary after such treatments. Although the involvement of cancer cells in the wound healing after treatments leads to the fast relapse, the cancer cells outside of the wound can also cause a slow recurrence of the tumor. Therefore, the absence of relapse after such treatments implies a slow-developing tumor that might not reach an observable size in the patient's lifetime. Conversely, a large solid tumor in a young patient suggests the presence of high fitness cancer cells and therefore a high likelihood of relapse after conventional therapies. Additionally, the location of remaining cancer cells after treatments is a very important factor in the recurrence time. The fastest recurrence happens when a high fitness cancer cell is located in the middle of the wound. However, the longest time to recurrence corresponds to cancer cells located outside of the wound's boundary.

2128: CGMD: An integrated database of Cancer Genes and Markers
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Posted to bioRxiv 10 Nov 2014

CGMD: An integrated database of Cancer Genes and Markers
4 downloads cancer biology

Pradeep K Jangampalli Adi, Kranthi K Konidala, Nanda K Yellapu, L Balasubramanyam, Bhaskar Matcha

Cancer is a dysregulation of apoptosis process a programmed cell death through which the cell number is tightly regulated. Many factors affect apoptosis including tumor genes (TGs). Moreover, several researchers identified TGs and demonstrated their functions in various types of tumors or normal samples. Surprisingly, it has also been indicated that the expression of tumor markers in the development of cancer type is also one of the important target sites for clinical applications. Therefore, integrating tumor genes and tumor markers with experimental evidences might definitely provide valuable information for further investigation of TGs and their crosstalk in cancer. To achieve this objective, we developed a database known as Cancer Gene Marker Database (CGMD) which integrates cancer genes and markers based on experimental background. The major goal of CGMD is to provide: 1) systemic treatment approaches and advancements of different cancer treatments in present scenario; 2) Pooling of different genes and markers with their molecular characterization and involvements in different pathways; 3) Free availability of CGMD at www.cgmd.in. The database consists of 309 genes plus 206 markers and also includes sequences of a list of 40 different human cancers and moreover, all the characterized markers have detailed descriptions in appropriate manner. CGMD extraction is collective and informative by using web resources like National Cancer Institute (NCI) and National Center for Biotechnology Information (NCBI), UniProtKB, KEGG and EMBOSS. CGMD provides updated literature regarding different cancer annotations and their detail molecular descriptions such as CpG islands, promoters, exons of cancer genes and their active sites, physico-chemical properties and also systematically represented the domains of characterized proteins.

2129: Genealogies in Growing Solid Tumors
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Posted to bioRxiv 07 Jan 2018

Genealogies in Growing Solid Tumors
4 downloads cancer biology

Duke U. Rick Durrett

Over the past two decades, the theory of tumor evolution has largely focused on the selective sweeps model. According to this theory, tumors evolve by a succession of clonal expansions that are initiated by driver mutations that have a fitness advantage over the resident types. A 2015 study of colon cancer by Sottoriva et al has suggested an alternative theory of tumor evolution, the so-called Big Bang model, in which all of the necessary driver mutations are acquired before expansion began, and the evolutionary dynamics within the expanding population are predominantly neutral. In this paper, we will describe a simple mathematical model inspired by work of Hallatschek and Nelson (2009) that makes quantitative predictions about spatial patterns of genetic variability. While this model has some success in matching observed patterns in two dimensions, it fails miserably in three dimensions. Despite this failure, we think the model analyzed here will be a useful first step in building an accurate model.

2130: Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dys-regulation of Epithelial-Mesenchymal Transition and subcellular re-localization of Beta-Catenin
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Posted to bioRxiv 13 Feb 2019

Deep proteomic analysis of Dnmt1 mutant/hypomorphic colorectal cancer cells reveals dys-regulation of Epithelial-Mesenchymal Transition and subcellular re-localization of Beta-Catenin
4 downloads cancer biology

Emily Bowler, Alex Smith-Vidal, Alex Lester, Joseph Bell, Zhenghe Wang, Chris Bell, Yihua Wang, Nullin Divecha, Paul Skipp, Rob M Ewing

Background: DNA methyltransferase I is the primary eukaryotic DNA methyltransferase engaged in maintenance of CpG DNA methylation patterns across the genome. Alteration of CpG methylation patterns and levels is a frequent and significant occurrence across many cancers, and targeted inhibition of Dnmt1 has become an approach of choice for select malignancies. There has been significant interest both in the methyltransferase activity as well as methylation-independent functions of Dnmt1. A previously generated hypomorphic allele of Dnmt1 in HCT116 colorectal cancer cells has become an important tool for understanding Dnmt1 function and how CpG methylation patterns are modulated across the genome. Colorectal cancer cells with the Dnmt1 hypomorphic allele carry a homozygous deletion of exons 3 to 5 of Dnmt1, resulting in greatly reduced Dnmt1 protein expression whilst still exhibiting a limited functional activity and methyltransferase ability. Although this cell model of reduced Dnmt1 levels and function have been used to study the downstream effects on the epigenome and transcriptome, the broader effects of the Dnmt1 hypomorph on the proteome and wider cell signalling are largely unknown. Results: In this study, we used quantitative proteomic analysis of nuclear-enriched samples of HCT116 Dnmt1 hypomorph cells to identify signalling pathways and processes dysregulated in the hypomorph cells as compared to wild-type HCT116 cells. Unexpectedly, we observed a clear signature of increased expression of Epithelial-to-Mesenchymal (EMT) in Dnmt1 hypomorph cells. We also observed reduced expression and sub-cellular re-localization of Beta-Catenin in Dnmt1 hypomorph cells. Expression of wild-type Dnmt1 in hypomorph cells or knock-down of wild-type Dnmt1 did not recapitulate or rescue the observed protein profiles in Dnmt1 hypomorph cells suggesting that hypomorphic Dnmt1 causes changes not solely attributable to Dnmt1 protein levels. Conclusions: In summary we present the first comprehensive proteomic analysis of the widely studied Dnmt1 hypomorph colorectal cancer cells and identify redistribution of Dnmt1 and its interaction partner Beta-Catenin as well as the dysregulation of EMT related processes and signalling pathways related to the development of a cancer stem cell phenotype.

2131: Hybrid Discrete-Continuum Cellular Automaton (HCA) model of Prostate to Bone Metastasis
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Posted to bioRxiv 15 Mar 2016

Hybrid Discrete-Continuum Cellular Automaton (HCA) model of Prostate to Bone Metastasis
4 downloads cancer biology

Arturo Araujo, David Basanta

Prostate to bone metastases induce a "vicious cycle" by promoting excessive osteoclast and osteoblast mediated bone degradation and formation that in turn yields factors that drive cancer growth. Recent advances defining the molecular mechanisms that control the vicious cycle have revealed new therapeutic targeting opportunities. However, given the complex temporal and simultaneous cellular interactions occurring in the bone microenvironment, assessing the impact of putative therapies is challenging. To this end, we have integrated biological and computational approaches to generate an accurate model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model faithfully reproduces the basic multicellular unit (BMU) bone coupling process and introduction of a single prostate cancer cell yields a vicious cycle that is similar in cellular composition and pathophysiology to models of prostate to bone metastasis.

2132: A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation
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Posted to bioRxiv 19 Feb 2018

A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation
3 downloads cancer biology

Marc A Vittoria, Elizabeth M Shenk, Kevin P. O’Rourke, Amanda F Bolgioni, Sanghee Lim, Victoria Kacprzak, Ryan J Quinton, Neil J Ganem

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ~40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that significantly inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

2133: Extinction Rates In Tumor Public Goods Games
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Posted to bioRxiv 04 May 2017

Extinction Rates In Tumor Public Goods Games
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Philip Gerlee, Philipp M. Altrock

Cancer evolution and progression are shaped by cellular interactions and Darwinian selection. Evolutionary game theory incorporates both of these principles, and has been proposed as a framework to understand tumor cell population dynamics. A cornerstone of evolutionary dynamics is the replicator equation, which describes changes in the relative abundance of different cell types, and is able to predict evolutionary equilibria. Typically, the replicator equation focuses on differences in relative fitness. We here show that this framework might not be sufficient under all circumstances, as it neglects important aspects of population growth. Standard replicator dynamics might miss critical differences in the time it takes to reach an equilibrium, as this time also depends on cellular turnover in growing but bounded populations. As the system reaches a stable manifold, the time to reach equilibrium depends on cellular death and birth rates. These rates shape the timescales, in particular in co-evolutionary dynamics of growth factor producers and free-riders. Replicator dynamics might be an appropriate framework only when birth and death rates are of similar magnitude. Otherwise, population growth effects cannot be neglected when predicting the time to reach an equilibrium, and cell type specific rates have to be accounted for explicitly.

2134: MiR-29b-1-5p is altered in BRCA1 mutant tumours and is a biomarker in basal- like breast cancer
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Posted to bioRxiv 10 May 2018

MiR-29b-1-5p is altered in BRCA1 mutant tumours and is a biomarker in basal- like breast cancer
3 downloads cancer biology

Michael J.G. Milevskiy, Gurveen K. Sandhu, Anna Wronski, Darren Korbie, Brooke L. Brewster, Annette Shewan, Stacey L. Edwards, Juliet D. French, Melissa A. Brown

Depletion of BRCA1 protein in mouse mammary glands results in defects in lactational development and increased susceptibility to mammary cancer. Extensive work has focussed on the role of BRCA1 in the normal breast and in the development of breast cancer, the cell of origin for BRCA1 tumours and the protein-coding genes altered in BRCA1 deficient cells. However, the role of non-coding RNAs in BRCA1-deficient cells is poorly understood. To evaluate miRNA expression in BRCA1 deficient mammary cells, RNA sequencing was performed on the mammary glands of Brca1 knockout mice. We identified 140 differentially expressed miRNAs, 9 of which were also differentially expressed in human BRCA1 breast tumours or familial non-BRCA1 patients and during normal gland development. We show that BRCA1 binds to putative cis-elements in promoter regions of the miRNAs and regulates their expression, and that four miRNAs (miR-29b-1-5p, miR-664, miR-16-2 and miR-744) significantly stratified the overall survival of basal-like tumours. Importantly the prognostic value of miR-29b-1-5p was higher in significance than several commonly used clinical biomarkers. These results emphasize the role of Brca1 in modulating expression of miRNAs and highlights the potential for BRCA1 regulated miRNAs to be informative biomarkers associated with BRCA1 loss and survival in breast cancer.

2135: Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3
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Posted to bioRxiv 15 Jun 2018

Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3
3 downloads cancer biology

Eric A Nollet, Sourik S Ganguly, Veronique V. Schulz, Anne Cress, Cindy K Miranti

Although castration-resistant prostate cancers no longer respond to anti-androgen therapies, the androgen receptor (AR) is still required to promote tumor survival. However, the signaling pathways downstream of AR that promote this survival are not well known. We recently identified an AR-dependent survival pathway whereby AR induction of integrin α6β1 and adhesion to laminin activates NF-κB/RelA signaling and Bcl-xL. This pathway acts in parallel with the PI3K/Akt pathway in Pten-null tumor cells such that combined inhibition of both PI3K and integrin α6β1 is required to kill tumor cells adherent to laminin. However, PTEN-null castration-resistant tumors were not effectively inhibited by this combination. We discovered that BNIP3, a hypoxia-induced BH3-only, pro-mitophagic Bcl2 family member, is induced by androgen in castration-resistant cells through integrin α6β1 signaling to HIF1α. Furthermore, castration-resistant cells adherent to laminin were much more efficient at inducing autophagy in response to androgen. Androgen blocked the ability of the PI3K inhibitor PX-866 to kill castration-resistant tumors, but this was reversed by loss of BNIP3. Although BNIP3 was dispensable for androgen-induced autophagy, its mitophagy function was required for BNIP3 to promote resistance to PI3K inhibition. Thus, adhesion to laminin triggers signaling through AR/α6β1/HIF1α in castration-resistant cells to drive the expression of BNIP3 and cooperates with AR/α6β1-mediated autophagy, both of which contribute to PI3K resistance through induction of mitophagy.

2136: The miR-338-3p involve in response to acute radiation syndrome by targeting DYRK2 in Tibet minipig
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Posted to bioRxiv 26 Dec 2018

The miR-338-3p involve in response to acute radiation syndrome by targeting DYRK2 in Tibet minipig
3 downloads cancer biology

Yu-Jue Wang, Min Yue, Kai Guo, Shao-Jie Wu, Tian Yuguang

MiRNAs as tumor suppressor have been identified in variety of cancer, but the role of miRNAs involve in ARS (acute radiation syndrome) in Tibet minipig are poorly understood. Here, in order to study the relationship between miRNAs pattern and ARS, microarray chip technology was used for screening of ARS related miRNAs in Tibet minipig small intestine. Not castrated male Tibetan minipig were chose as animal model (n = 54), and exposed to the total body X-ray radiation at 0, 2, 5, 8, 11, 14 Gy (n= 9/ group), The total miRNA was extracted and hybridized to microarray chip. The HIC cell proliferation was evaluated by CCK8 assay, and the apoptosis was evaluated by flow-cytometric after X-ray irradiation. The athymic mice subcutaneous injection was used to research tumor formation. The bioinformatics tools and luciferase assay was applied to detect the relationship between miR-338-3p and its target. In total, 63 specific miRNAs were differentially regulated in the exposed small intestin tissues with 3, 24, 29, 25, and 32 miRNAs identified per dose-level (2, 5, 8, 11, and 14 Gy, respectively). MiR-338-3p was commonly regulated at 5, 8, 11, and 14 Gy dose levels and was used for cell assay. MiR-338-3p can regulates. HIC cell proliferation and apoptosis after X-ray irradiation administration. DYRK2 is one of target of miR-338-3p and suppressed by X-ray irradiation administration. Our study first revealed the ARS associated miRNA signatures were generally dose-specific, and miR-338-3p involve in response to ARS by targeting DYRK2 and may be used as early immunological response biomarker for ARS research.

2137: Significantly different expression levels of microRNAs associated with vascular invasion in hepatocellular carcinoma and their prognostic significance after surgical resection
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Posted to bioRxiv 01 May 2019

Significantly different expression levels of microRNAs associated with vascular invasion in hepatocellular carcinoma and their prognostic significance after surgical resection
3 downloads cancer biology

Sung Kyu Song, Woon Yong Jung, Yong Keun Park, Chul-Woon Chung, Yongkeun Park

Background: Although gross vascular invasion (VI) has prognostic significance in patients with hepatocellular carcinoma (HCC) who have undergone hepatic resection, few studies have investigated the relationship between gross VI and aberrant expression of microribonucleic acids (miRNAs and miRs). Thus, the objective of this study was to identify miRNAs selectively expressed in HCC with gross VI and investigate their prognostic significance. Materials and Methods: Eligible two datasets (accession number: GSE20594 and GSE67140) were collected from the National Center for Biotechnology Information's (NCBI) Gene Expression Omnibus (GEO) database to compare miRNAs expression between HCC with and without gross VI. Differentially expressed miRNAs were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Prognostic significance and predicted functions of selected miRNAs for HCC were also investigated. Results: Thirty-five miRNAs were differentially expressed between HCC with and without gross VI in both datasets. Among them, four miRNAs were validated using TCGA database. miR-582 was upregulated to a greater extent while miR-99a, miR-100, and miR-148a were downregulated to a greater extent in patients with HCC and gross VI than in those with HCC but no VI. Receiver operating characteristic (ROC) curve analysis showed discriminatory power of these miRNAs in predicting gross VI. Multivariate survival analysis revealed that types of surgery, advanced tumor node metastasis (TNM) stage, and miR-100 underexpression were independently associated with tumor recurrence. It also revealed that types of surgery, advanced TNM stage, miR-100 underexpression, and miR-582 overexpression were independent risk factors for overall survival (OS) after hepatic resection for HCC. A text mining analysis revealed that these miRNAs were linked to multifaceted hallmarks of cancer, including “invasion and metastasis.” Conclusions: miR-100 underexpression and miR-582 overexpression were associated with gross VI and poor survival of patients after hepatic resection for HCC.

2138: Magnetic resonance imaging for characterization of a chick embryo model of cancer cell metastases
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Posted to bioRxiv 22 Nov 2017

Magnetic resonance imaging for characterization of a chick embryo model of cancer cell metastases
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Anne Herrmann, Arthur Taylor, Patricia Murray, Harish Poptani, Violaine SEE

Background: Metastasis is the most common cause of death for cancer patients, hence its study has rapidly expanded over the past few years. To fully understand all the steps involved in metastatic dissemination, in vivo models are required, of which murine ones are the most common. Therefore pre-clinical imaging methods have mainly been developed for small mammals. However, the potential of preclinical imaging techniques such as magnetic resonance imaging (MRI) to monitor cancer growth and metastasis in non-mammalian in vivo models is not commonly used. We have here used MRI to measure primary neuroblastoma tumour size and presence of metastatic dissemination in a chick embryo model. We compared its sensitivity and accuracy to end-point fluorescence detection. Methods: Human neuroblastoma cells were labelled with GFP and micron-sized iron particles (MPIOs) and implanted on the extraembryonic chorioallantoic membrane of the chick embryo at E7. T2 RARE, T2 weighted FLASH as well as time-of-flight MR angiography imaging was applied at E14. Primary tumours as well as metastatic deposits in the chick embryo were dissected post imaging to compare with MRI results. Results: MPIO labelling of neuroblastoma cells allowed in ovo observation of the primary tumour and tumour volume measurement non-invasively over time. Moreover, T2 weighted and FLASH imaging permitted the detection of very small metastatic deposits in the chick embryo. Conclusions: The use of contrast agents enabled the detection of metastatic deposits of neuroblastoma cells in a chick embryo model, thereby reinforcing the potential of this cost efficient and convenient, 3R compliant, in vivo model for cancer research.

2139: Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation
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Posted to bioRxiv 11 Jul 2018

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation
3 downloads cancer biology

Antoinette van Weverwijk, Nikolaos Koundouros, Marjan Iravani, Matthew Ashenden, Qiong Gao, George Poulogiannis, Ute Jungwirth, Clare M. Isacke

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10-High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10-High-enhanced metastatic colonisation with no impact on AKR1B10-Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.

2140: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
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Posted to bioRxiv 28 Sep 2017

ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
3 downloads cancer biology

Chang S. Chan, Saurabh V Laddha, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy A Chan, David S Klimstra, C. David Allis, Laura H. Tang

The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

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