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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 90,007 bioRxiv papers from 385,381 authors.

Most downloaded bioRxiv papers, since beginning of last month

in category cancer biology

3,098 results found. For more information, click each entry to expand.

2121: FoxN1-dependent thymic epithelial cells promote T-cell leukemia development
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Posted to bioRxiv 11 Jan 2018

FoxN1-dependent thymic epithelial cells promote T-cell leukemia development
10 downloads cancer biology

Marinella N. Ghezzo, Mónica T. Fernandes, Rui S Machado, Ivette Pacheco-Leyva, Marta A.S. Araújo, Ravi K. Kalathur, Matthias E. Futschik, Nuno L. Alves, Nuno R. dos Santos

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. The role of thymic microenvironmental cells and stromal factors in thymocyte malignant transformation and T-ALL development remains little explored. Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis. Immunofluorescence analyses showed that thymic lymphomas presented epithelial areas characterized by keratin 5 and keratin 8 expression, adjacently to keratin-negative, epithelial-free areas. Both keratin-positive and -negative areas stained conspicuously with ER-TR7 (a fibroblast marker), laminin, and CD31 (an endothelial cell marker). Besides keratin 5, keratin-positive areas were also labeled by the Ulex Europaeus agglutinin-1 medullary thymic epithelial cell (TEC) marker. To assess whether TECs are important for T-ALL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation. In contrast to nude homozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nu compound mice both emergence of malignant cells in pre-leukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays leukemic cell expansion in the thymus of recipient Foxn1+/nu mice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.

2122: The PTPRT pseudo-phosphatase domain is a denitrase
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Posted to bioRxiv 22 Dec 2017

The PTPRT pseudo-phosphatase domain is a denitrase
10 downloads cancer biology

Yiqing Zhao, Shuliang Zhao, Yujun Hao, Benlian Wang, Peng Zhang, Xiujing Feng, Yicheng Chen, Jing Song, John Mieyal, Sanford Markowitz, Rob M Ewing, Ronald A. Conlon, Masaru Miyagi, Zhenghe Wang

Protein tyrosine nitration occurs under both physiological and pathological conditions. However, enzymes that remove this protein modification have not yet been identified. Here we report that the pseudo-phosphatase domain of protein tyrosine receptor T (PTPRT) is a denitrase that removes nitro-groups from tyrosine residues in paxillin. PTPRT normally functions as a tumor suppressor and is frequently mutated in a variety of human cancers including colorectal cancer. We demonstrate that some of the tumor-derived mutations located in the pseudo-phosphatase domain impair the denitrase activity. Moreover, PTPRT mutant mice that inactivate the denitrase activity are susceptible to carcinogen-induced colon tumor formation. This study uncovers a novel enzymatic activity that is involved in tumor suppression.

2123: Programming of macrophages by apoptotic cancer cells inhibits cancer progression through exosomal PTEN and PPARγ ligands
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Posted to bioRxiv 10 Nov 2017

Programming of macrophages by apoptotic cancer cells inhibits cancer progression through exosomal PTEN and PPARγ ligands
10 downloads cancer biology

Yong-Bae Kim, Young-Ho Ahn, Jin-Hwa Lee, Jihee Lee Kang

Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits epithelial-mesenchymal transition (EMT), migration, and invasion of cancer cells with the acquisition of cancer-stem–like traits. Apoptotic 344SQ (ApoSQ) cell-induced PPARγ activity in macrophages caused increased PTEN levels, secreted in exosomes. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in recipient 344SQ cells, restore cellular polarity, and exert anti-EMT and anti-invasive effects. The CM which deficient of PPARγ ligands could not reverse the suppression of PPARγ activity and PTEN and consequently failed to the prevent EMT process. Moreover, single injection of ApoSQ cells inhibited lung metastasis in syngeneic mice with enhanced PPARγ/PTEN signaling both in tumor-associated macrophages and tumor cells. PPARγ antagonist GW9662 reversed PTEN signaling and anti-metastatic effect. Thus, apoptotic cancer cell therapy may offer a new strategy for the prevention of metastasis.

2124: The Neutrophil-to-Lymphocyte Ratio as a Prognostic Indicator in Head and Neck Cancer: A Systematic Review and Meta-Analysis
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Posted to bioRxiv 09 Nov 2017

The Neutrophil-to-Lymphocyte Ratio as a Prognostic Indicator in Head and Neck Cancer: A Systematic Review and Meta-Analysis
10 downloads cancer biology

Tristan Tham, Yonatan Bardash, Saori Wendy Herman, Peter D. Costantino

Background: The aim of this systematic review and meta-analysis was to investigate the relationship between the Neutrophil-to-Lymphocyte Ratio (NLR) and prognosis in HNC. Methods: Studies were identified from Pubmed, Embase, Scopus, and the Cochrane Library. A systematic review and meta-analysis were performed to generate the pooled hazard ratios (HR) for overall survival (OS), disease free survival (DFS), and progression free survival (PFS). Results: Our analysis combined the results of over 6770 patients in 26 cohorts (25 studies). The pooled data demonstrated that an elevated NLR significantly predicted poorer OS, DFS, and PFS. Heterogeneity was found for OS, PFS, and marginally for DFS. Subgroup analysis in OS demonstrated that elevated NLR remained an indicator of poor prognosis. Conclusions: Elevated pretreatment NLR is a prognostic marker for HNC. It represents a simple and easily obtained marker that could be used to stratify groups of high-risk patients that might benefit from adjuvant therapy.

2125: Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
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Posted to bioRxiv 08 Nov 2017

Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
10 downloads cancer biology

Aurélie S Cazet, Mun N. Hui, Benjamin L. Elsworth, Sunny Z. Wu, Daniel Roden, Chia-Ling Chan, Joanna N. Skhinas, Raphaël Collot, Jessica Yang, Kate Harvey, M. Zahied Johan, Caroline Cooper, Radhika Nair, David Herrmann, Andrea McFarland, Nian-Tao Deng, Manuel Ruiz-Borrego, Federico Rojo, José M. Trigo, Susana Bezares, Rosalía Caballero, Elgene Lim, Paul Timpson, Sandra O’Toole, D. Neil Watkins, Thomas R Cox, Michael Samuel, Miguel Martín, Alexander Swarbrick

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC.

2126: Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site.
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Posted to bioRxiv 05 Feb 2020

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site.
10 downloads cancer biology

Daniel S McCracken, Hongzhuang Peng, Kasirajan Ayyanathan, Yike Lindy Jiang, Sarah Welsh, Jing Yang, Eileen J. Kennedy, Frank J. Rauscher, Alessandro Gardini

Epithelial-Mesenchymal transition (EMT) of primary tumor cells is a critical trans-differentiation event that contributes to dissemination and metastasis. The process of EMT is controlled by specific DNA-binding transcription factors (TFs) that reprogram the tumor transcriptome. In particular, the canonical EMT-TFs Twist and Snail can induce an EMT program when overexpressed in cancer cells, and both are found upregulated in metastatic cancers. Twist and Snail bind DNA directly, by recognition to variants of the E-Box sequence CANNTG. However, it is unclear how this binding is regulated. We have used a biochemical approach to dissect DNA binding and protein-protein interactions that occur amongst these proteins. We find that Twist preferentially recognizes a dyad repeat of E-boxes that are not directly bound by Snail. Our data suggest that Twist use its WR domain to recruit Snail into a binding complex through the Snail zinc-finger motifs. We analyzed Twist-Snail complexes in the breast carcinoma cell line SUM1315 and found evidence that it contains an additional protein partner, Sox9. Notably, we report that a native Twist complex can be displaced from its dyad binding site by consensus DNA binding sites for Snail and Sox9 even though these proteins do not contact the Twist dyad site. Taken together, our findings suggest that Snail and Sox9 interact with Twist to regulate its DNA binding ability via protein-protein interactions, thereby allosterically regulating Twist DNA binding. We designate this ternary complex EMTosome. These results may inform efforts to therapeutically target the EMT program in order to target cancer metastasis.

2127: Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy
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Posted to bioRxiv 28 Sep 2017

Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib/letrozole combination cancer therapy
10 downloads cancer biology

Benedikt Warth, Philipp Raffeiner, Ana Granados, Tao Huan, Mingliang Fang, Erica M. Forsberg, H. Paul Benton, Laura Goetz, Caroline H. Johnson, Gary Siuzdak

Recently, the palbociclib/letrozole combination therapy was granted accelerated FDA approval for the treatment of estrogen receptor (ER) positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein, and the estrogenic mycotoxin zearalenone on this treatment. A global metabolomics approach was applied to unravel metabolite and pathway modifications. The results clearly showed that the combined effects of palbociclib and letrozole on cellular metabolism were far more pronounced than that of each agent alone and potently influenced by xenoestrogens. This behavior was confirmed in proliferation experiments and functional assays. Specifically, amino acids and central carbon metabolites were attenuated while higher abundances were observed for fatty acids and most nucleic acid related metabolites. Interestingly, exposure to model xenoestrogens appeared to partially counteract these effects.

2128: Expanding discovery from cancer genomes by integrating protein network analyses with in vivo tumorigenesis assays
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Posted to bioRxiv 19 Jun 2017

Expanding discovery from cancer genomes by integrating protein network analyses with in vivo tumorigenesis assays
10 downloads cancer biology

Heiko Horn, Michael S Lawrence, Candace R. Chouinard, Yashaswi Shrestha, Jessica Xin Hu, Elizabeth Worstell, Emily Shea, Nina Ilic, Eejung Kim, Atanas Kamburov, Alireza Kashani, William C. Hahn, Joshua D. Campbell, Jesse S. Boehm, Gad Getz, Kasper Lage

Approaches that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes, but are challenging to validate at scale and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks and data from 4,742 tumor exomes and used it to accurately classify known driver genes in 60% of tested tumor types and to predict 62 new candidates. We designed a quantitative experimental framework to compare the in vivo tumorigenic potential of NetSig candidates, known oncogenes and random genes in mice showing that NetSig candidates induce tumors at rates comparable to known oncogenes and 10-fold higher than random genes. By reanalyzing nine tumor-inducing NetSig candidates in 242 patients with oncogene-negative lung adenocarcinomas, we find that two (AKT2 and TFDP2) are significantly amplified. Overall, we illustrate a scalable integrated computational and experimental workflow to expand discovery from cancer genomes.

2129: Oncogenic addiction to high 26S proteasome levels
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Posted to bioRxiv 30 Oct 2017

Oncogenic addiction to high 26S proteasome levels
10 downloads cancer biology

Peter Tsvetkov, Julia Adler, Nadav Myers, Assaf Biran, Nina Reuven, Yosef Shaul

Proteasomes are large intracellular complexes responsible for the degradation of cellular proteins. The altered protein homeostasis of cancer cells results in increased dependency on proteasome function. There are several different proteasome complexes that may be assembled in cells, with the 20S catalytic core common to them all. 20S proteasomes can function in isolation, or as part of larger complexes (26S) with regulatory particles (RP) such as the 19S that is needed for the targeting and processing of ubiquitinated substrates. Proteasome inhibitors target the catalytic barrel (20S) and thus this inhibition does not allow the deconvolution of the distinct roles of 20S vs. 26S proteasomes in cancer progression. We examined the degree of dependency of cancer cells specifically to the level of the 26S proteasome complex. We found that oncogenic transformation of human and mouse immortalized cells with mutant Ras induced a strong increase in the translation of the 26S proteasome subunits, giving rise to high 26S complex levels. We show that depletion of a single subunit of the 19S RP was sufficient to significantly reduce the 26S proteasome level and lower the cellular 26S/20S ratio. We further demonstrate that the accumulated 26S proteasome was essential for the viability of the transformed cells. Moreover, the viability of 20 different cancer cell lines, but not normal human fibroblasts, was severely compromised upon specific 26S proteasome suppression regardless of their p53 status. Suppression of 26S activated the UPR and Caspase-3, which at least partially explains the cell-killing effect. Morphologically, suppression of the 26S proteasome resulted in cytoplasm shrinkage and nuclear deformation. Thus, the tumor cell-specific addiction to high 26S proteasome levels sets the stage for future strategies in cancer therapy.

2130: Fibroblasts from metastatic sites induce broad-spectrum drug desensitization via modulation of mitochondrial priming
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Posted to bioRxiv 02 Oct 2017

Fibroblasts from metastatic sites induce broad-spectrum drug desensitization via modulation of mitochondrial priming
10 downloads cancer biology

Benjamin D. Landry, Thomas Leete, Ryan Richards, Peter Cruz-Gordillo, Gary Ren, Alyssa D Schwartz, Shelly R Peyton, Michael J. Lee

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor micro-environment. Using a large-scale co-culture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not cell intrinsic, but rather a product of tumor-stroma interactions. Additionally, we find that fibroblast cells influence tumor drug response in two distinct and divergent manners, which were predicable based on the anatomical origin from which the fibroblasts were harvested. These divergent phenotypes result from modulation of mitochondrial priming of tumor cells, caused by secretion of inflammatory cytokines, such as IL6 and IL8, from stromal cells.

2131: Adenylate kinase-4 modulates oxidative stress and stabilizes HIF-1α to drive lung cancer metastasis
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Posted to bioRxiv 01 Oct 2017

Adenylate kinase-4 modulates oxidative stress and stabilizes HIF-1α to drive lung cancer metastasis
10 downloads cancer biology

Yi-Hua Jan, Tsung-Ching Lai, Chih-Jen Yang, Yuan-Feng Lin, Ming-Shyan Huang, Michael Hsiao

Disrupting signaling axes that are essential for tumor metastasis may provide therapeutic opportunity to cure cancer. We previously identified adenylate kinase 4 (AK4) as a biomarker of metastasis in lung cancer. Here we analyze AK4-associated metabolic gene signature and reveal HIF-1α is transcriptionally activated and associated with poor prognosis in lung adenocarcinoma patients. Overexpression of AK4 shifts metabolism towards aerobic glycolysis and elevates intracellular reactive oxygen species (ROS), which stabilizes and exaggerates HIF1-α protein expression and concurrently drives epithelial-to-mesenchymal transition (EMT) in hypoxia. Furthermore, overexpression of AK4 reduces hypoxic necrosis in tumors and promotes liver metastasis in vivo. Connectivity map analysis of AK4 gene signature identifies Withaferin-A as a potential compound to inhibit AK4-HIF-1α signaling axis, which then shows promising anti-metastatic potency in an orthotopic xenograft model of lung cancer. Our findings offer an alternative strategy to impair lung cancer metastasis via targeting AK4-HIF-1α axis.

2132: 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
10 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.

2133: A potential link between tuberculosis and lung cancer through non-coding RNAs
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Posted to bioRxiv 13 Sep 2017

A potential link between tuberculosis and lung cancer through non-coding RNAs
10 downloads cancer biology

Debmalya Barh, Sandeep Tiwari, Ranjith N. Kumavath, Vasco Azevedo

Pulmonary tuberculosis caused by Mycobacterium and lung cancer are two major causes of deaths worldwide and the former increases the risk of developing lung cancer. However, the precise molecular mechanism of Mycobacterium associated increased risk of lung cancer is not entirely understood. Here, using in silico approaches, we show that hsa-mir-21 and M. tuberculosis sRNA_1096 and sRNA_1414 could play important roles in the pathogenesis of both these diseases. Further, we postulated a Genetic remittance hypothesis where these sRNAs may play important roles. The sRNA_1096 could be involved in tuberculosis through multiple infectious processes, and if transferred to the host, it may activate the TLR8 mediated pro-metastatic inflammatory pathway by acting as a ligand to TLR8 similar to the mir-21 leading to lung tumorigenesis and chemo-resistance. Analogous to SH3GL1, it may also regulate cell cycle. On the other hand, sRNA_1414 is probably involved in survivability and drug response of the pathogen. However, it may be a metastatic factor for lung cancer providing EPS8L1 and SORBS1 like functions upon remittance. Further, all these three non-coding RNAs are predicted to act in rifampicin resistance in Mycobacterium. Currently, we are applying robust bioinformatics strategies and conducting experimental validations to confirm our in-silico findings and hypothesis.

2134: Extinction Rates In Tumor Public Goods Games
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Posted to bioRxiv 04 May 2017

Extinction Rates In Tumor Public Goods Games
10 downloads cancer biology

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.

2135: Insulin Does Not Augment In Vitro Tumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner
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Posted to bioRxiv 28 Jul 2017

Insulin Does Not Augment In Vitro Tumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner
10 downloads cancer biology

Tao Liao, Xiao-Hui Li, Yan-Ping Chen, Li-Li Tan, Ji-Da Zhang, Xin-An Huang, Qin Xu, Sui-Qing Huang, Chang-Qing Li, Qing-Ping Zeng

Background: Whether insulin enhances or represses tumor cell proliferation remains debating and inconclusive although epidemiological data indicated insulin use raises a risk of cancer incidence in patients with diabetes mellitus (DM). Methodology/Principle Findings: We cultured rat pituitary adenoma cells in a high-glucose medium to simulate hyperglycemia occurring in DM patients. Upon incubation with or without insulin, repressed tumor cell proliferation and downregulated tumor marker expression occur accompanying with mitigated oxidative stress and compromised apoptosis. Mechanistically, insulin resistance-abrogated glucose uptake was suggested to create an intracellular low-glucose milieu, leading to cellular starvation resembling calorie restriction (CR). While downregulation of insulin-like growth factor 1 (IGF-1) occurring in CR was validated, oncogene downregulation and tumor suppressor gene upregulation seen in CR was also replicated by NOS2 knockdown. Conclusions/Significance: Cellular starvation can exert CR-like anti-tumor effects regardless of insulin presence or absence.

2136: DNA 5-Hydroxymethylcytosines from Cell-free Circulating DNA as Diagnostic Biomarkers for Human Cancers
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Posted to bioRxiv 13 Jul 2017

DNA 5-Hydroxymethylcytosines from Cell-free Circulating DNA as Diagnostic Biomarkers for Human Cancers
10 downloads cancer biology

Wenshuai Li, Xu Zhang, Xingyu Lu, Lei You, Yanqun Song, Zhongguang Luo, Jun Zhang, Ji Nie, Wanwei Zheng, Diannan Xu, Yaping Wang, Yuanqiang Dong, Shulin Yu, Jun Hong, Jianping Shi, Hankun Hao, Fen Luo, Luchun Hua, Peng Wang, Xiaoping Qian, Fang Yuan, Lianhuan Wei, Ming Cui, Taiping Zhang, Quan Liao, Menghua Dai, Ziwen Liu, Ge Chen, Katherine Meckel, Sarbani Adhikari, Guifang Jia, Marc B. Bissonnette, Xinxiang Zhang, Yupei Zhao, Wei Zhang, Chuan He, Jie Liu

DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals (1, 2). Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology (3), we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and in genomic DNA of paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures in cfDNA were identified with specificity for different cancers. 5hmC-based biomarkers of circulating cfDNA demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to 5hmC biomarkers from tissue biopsies. This new strategy could lead to the development of effective blood-based, minimally-invasive cancer diagnosis and prognosis approaches.

2137: Mutation-Profile-Based Methods for Understanding Selection Forces in Cancer Somatic Mutations: A Comparative Analysis
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Posted to bioRxiv 20 Jun 2015

Mutation-Profile-Based Methods for Understanding Selection Forces in Cancer Somatic Mutations: A Comparative Analysis
10 downloads cancer biology

Zhan Zhou, Yangyun Zou, Gangbiao Liu, Jingqi Zhou, Jingcheng Wu, Shimin Zhao, Zhixi Su, Xun Gu

Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes (CN/CS) and normal populations (pN/pS). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels. Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased CN/CS values of human genes in cancer genomes compared with the pN/pS values in human populations. The CN/CS values also contribute to the improved classification of cancer genes and a better understanding of the onco-functionalization of cancer genes during oncogenesis. The use of our computational pipeline to identify cancer-specific positively and negatively selected genes may provide useful information for understanding the evolution of cancers and identifying possible targets for therapeutic intervention.

2138: A compendium of co-regulated protein complexes in breast cancer reveals collateral loss events
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Posted to bioRxiv 26 Jun 2017

A compendium of co-regulated protein complexes in breast cancer reveals collateral loss events
10 downloads cancer biology

Colm Ryan, Susan Kennedy, Ilirjana Bajrami, David Matallanas, Christopher J. Lord

Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and composition varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 258 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or over-expressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was evident from proteomic, but not transcriptomic, profiles suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1) was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss.

2139: Impairment of mitochondrial respiratory function as an early biomarker of apoptosis induced by growth factor removal
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Posted to bioRxiv 18 Jun 2017

Impairment of mitochondrial respiratory function as an early biomarker of apoptosis induced by growth factor removal
10 downloads cancer biology

Hélène Lemieux, Patrick Subarsky, Christine Doblander, Martin Wurm, Jakob Troppmair, Erich Gnaiger

Intracellular signaling pathways not only control cell proliferation and survival, but also regulate the provision of cellular energy and building blocks through mitochondrial and non-mitochondrial metabolism. Wild-type and oncogenic RAF kinases have been shown to prevent apoptosis following the removal of interleukin 3 (IL-3) from mouse pro-myeloid 32D cells by reducing mitochondrial reactive oxygen species production. To study primary effects of RAF on mitochondrial energy metabolism, we applied high-resolution respirometry after short-term IL-3 deprivation (8 h), before 32D cells show detectable signs of cell death. Respiration in intact 32D cells was suppressed as an early event following removal of IL-3, but remained more stable in 32D cells expressing the v-RAF oncogene. In permeabilized 32D cells deprived of IL-3, respiratory capacities of the NADH-pathway, the convergent NADH&succinate-pathway, and Complex IV activity were decreased compared to cells grown in the presence of IL-3, whereas succinate-supported respiration remained unchanged, consistent with control by Complex IV. The apparent Complex IV excess capacity was zero above NADH&succinate-pathway capacity reconstituting tricarboxylic acid cycle function. In comparison, electron flow reached only 60% when supported by succinate alone through Complexes II, III and IV, and was therefore relatively insensitive to Complex IV injuries up to a threshold of 40% inhibition. A slight increase in respiration following addition of cytochrome c, a marker of mitochondrial outer membrane leakage, was present after IL-3 depletion, indicating mitochondrial fragility. Our results highlight a novel link between the key mitogenic and survival kinase CRAF and mitochondrial energy homeostasis.

2140: Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple
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Posted to bioRxiv 12 Jun 2017

Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple
10 downloads cancer biology

Nicolas Aznar, Ying Dunkel, Nina Sun, Kendall Satterfield, Fang He, Inmaculada Lopez-Sanchez, Majid Ghassemian, Debashis Sahoo, Irina Kufareva, Pradipta Ghosh

Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are the Wnt/Frizzled(FZD), growth factor-receptor tyrosine kinases (RTKs), and G-proteins/GPCRs. Here we identify Daple, a modulator of trimeric G-proteins and a Dishevelled(Dvl)-binding protein as an unexpected point of convergence for all three cascades. Daple-dependent activation of Gαi and enhancement of non-canonical Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but is also hijacked by growth factor-RTKs to fuel tumor progression. Phosphorylation of Daple by both RTKs and non-RTKs triggers Gαi activation and potentiates non-canonical Wnt signals that trigger epithelial-mesenchymal transition. In patients with colorectal cancers, concurrent upregulation of Daple and the prototype RTK, EGFR, carries poor prognosis. This work defines a novel growth factor↔G-protein↔Wnt crosstalk paradigm in cancer biology.

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