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Cancer Research

Lisa Liang, Ludivine Coudière Morrison, Nazanin Tatari, Margaret Stromecki, Agnes Fresnoza, Christopher J Porter, Marc R Del Bigio, Cynthia Hawkins, Jennifer A Chan, Timothy C Ryken, Michael D Taylor, Vijay Ramaswamy, Tamra E Werbowetski-Ogilvie
The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, co-existing cellular subsets both in vitro and in vivo...
June 21, 2018: Cancer Research
Young Kyuen Im, Ouafa Najyb, Simon-Pierre Gravel, Shawn McGuirk, Ryuhjin Ahn, Daina Avizonis, Valérie Chénard, Valerie Sabourin, Jesse Hudson, Tony Pawson, Ivan Topisirovic, Michael N Pollak, Julie St-Pierre, Josie Ursini-Siegel
The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcription factor, a central regulator of mitochondrial metabolism...
June 21, 2018: Cancer Research
Myron G Best, Pieter Wesseling, Thomas Wurdinger
Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels...
June 19, 2018: Cancer Research
Suvi Luoto, Ismaïl Hermelo, Elisa M Vuorinen, Paavo Hannus, Juha Kesseli, Matti Nykter, Kirsi J Granberg
The immunosuppressive microenvironment in glioblastoma (GBM) prevents an efficient antitumoral immune response and enables tumor formation and growth. Although an understanding of the nature of immunosuppression is still largely lacking, it is important for successful cancer treatment through immune system modulation. To gain insight into immunosuppression in GBM, we performed a computational analysis to model relative immune cell content and type of immune response in each GBM tumor sample from The Cancer Genome Atlas RNA-seq dataset...
June 19, 2018: Cancer Research
Gianmarco Pallavicini, Francesco Sgro, Francesca Garello, Mattia Falcone, Valeria Bitonto, Gaia E Berto, Federico T Bianchi, Marta Gai, Alessandra Ma Chiotto, Miriam Filippi, Juan C Cutrin, Ugo Ala, Enzo Terreno, Emilia Turco, Ferdinando Di Cunto
Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB consists of surgery followed by irradiation of the whole neuraxis and high-dose multi-agent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting MB growth without disturbing brain development is needed. Citron kinase protein (CITK), encoded by primary microcephaly gene MCPH17, is required for normal proliferation and survival of neural progenitors...
June 19, 2018: Cancer Research
Hung-Hsi Chen, Hsin-I Yu, Muh-Hwa Yang, Woan-Yuh Tarn
Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes including ATF4-modulated genes in an aggressive OSCC cell line...
June 19, 2018: Cancer Research
Shourong Wu, Huimin Wang, Yanjun Li, Yudan Xie, Can Huang, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim
Tumor cells alter their metablosim to meet their demand for macromolecules, support a high rate of proliferation as well as cope with oxidative stress. The transcription factor yin yang 1 (YY1) is upregulated in various types of tumors and is crucial for tumor cell proliferation and metastasis. However, its role in tumor cell metabolic reprogramming is poorly understood. Here we show that YY1 alters tumor cell metabolism by activating glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway...
June 19, 2018: Cancer Research
Jialing Zhang, Tony Chen, Xinping Yang, Hui Cheng, Stephan S Späth, Paul E Clavijo, Jianhong Chen, Christopher Silvin, Natalia Issaeva, Xiulan Su, Wendell G Yarbrough, Christina M Annunziata, Zhong Chen, Carter Van Waes
Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF-receptor-associated-factor-3 (TRAF3)...
June 19, 2018: Cancer Research
Kimberley Kolijn, Esther I Verhoef, Marcel Smid, René Böttcher, Guido W Jenster, Reno Debets, Geert Jlh van Leenders
Cancer invasion and metastasis are driven by epithelial-to-mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in prostate cancer patients. We performed laser capture micro-dissection of matched N-cadherin-positive and -negative prostate cancer areas from patient samples (n=8) followed by RNA sequencing...
June 19, 2018: Cancer Research
Tomoo Osumi, Shin-Ichi Tsujimoto, Moe Tamura, Meri Uchiyama, Kazuhiko Nakabayashi, Kohji Okamura, Masanori Yoshida, Daisuke Tomizawa, Akihiro Watanabe, Hiroyuki Takahashi, Tsukasa Hori, Shohei Yamamoto, Kazuko Hamamoto, Masahiro Migita, Hiroko Ogata-Kawata, Toru Uchiyama, Hiroe Kizawa, Hitomi Ueno-Yokohata, Ryota Shirai, Masafumi Seki, Kentaro Ohki, Junko Takita, Takeshi Inukai, Seishi Ogawa, Toshio Kitamura, Kimikazu Matsumoto, Kenichiro Hata, Nobutaka KIyokawa, Susumu Goyama, Motohiro Kato
Translocations of retinoic acid receptor-α (RARA), typically PML-RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1-RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified...
June 19, 2018: Cancer Research
Xiaoliang Wang, Andrew T Chan, Martha L Slattery, Jenny Chang-Claude, John D Potter, Steven Gallinger, Bette Caan, Johanna W Lampe, Polly A Newcomb, Niha Zubair, Li Hsu, Robert E Schoen, Michael Hoffmeister, Hermann Brenner, Loic Le Marchand, Ulrike Peters, Emily White
Nonsteroidal anti-inflammatory drugs (NSAIDs) use has consistently been associated with lower risk of colorectal cancer (CRC); however, studies showed inconsistent results on which cohort of individuals may benefit most. We performed multivariable logistic regression analysis to systematically test for the interaction between regular use of NSAIDs and other lifestyle and dietary factors on CRC risk among 11,894 cases and 15,999 controls. Fixed-effects meta-analyses were used for stratified analyses across studies for each risk factor and to summarize the estimates from interactions...
June 19, 2018: Cancer Research
Adam G Sowalsky, Huihui Ye, Manoj Bhasin, Eliezer M Van Allen, Massimo Loda, Rosina T Lis, Laleh Montaser-Kouhsari, Carla Calagua, Fen Ma, Joshua W Russo, Rachel J Schaefer, Olga S Voznesensky, Zhenwei Zhang, Glenn J Bubley, Bruce Montgomery, Elahe A Mostaghel, Peter S Nelson, Mary-Ellen Taplin, Steven P Balk
Primary prostate cancer (PCa) can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant PCa (mCRPC) remains unclear. In this study, we microdissected residual PCa foci in radical prostatectomies from 18 men treated with neoadjuvant intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors with no increase in neuroendocrine differentiation...
June 19, 2018: Cancer Research
Hong-Quan Duong, Ivan Nemazanyy, Florian Rambow, Seng Chuan Tang, Sylvain Delaunay, Lars Tharun, Alexandra Florin, Reinhard Büttner, Daniel Van Daele, Pierre Close, Jean Christophe Marine, Kateryna Shostak, Alain Chariot
MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis...
June 18, 2018: Cancer Research
Lu-Nan Qi, Bang-De Xiang, Fei-Xiang Wu, Jia-Zhou Ye, Jian-Hong Zhong, Yan-Yan Wang, Yuan-Yuan Chen, Zu-Shun Chen, Liang Ma, Jie Chen, Wen-Feng Gong, Ze-Guang Han, Yan Lu, Jin-Jie Shang, Le-Qun Li
To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) patients, we used an advanced CanPatrol™ CTC-enrichment technique and in situ hybridization (ISH) to enrich and classify CTC from blood samples. 101 of 112 (90.18%) HCC patients were CTC-positive, even with early-stage disease. CTC were also detected in 2 of 12 hepatitis B virus (HBV) patients, both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis...
June 18, 2018: Cancer Research
Paradesi Naidu Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Natesan Ramakrishnan, Carl G Engelke, Vijaya L Dommeti, Pranathi M Krishnamurthy, Archana Nallasivam, Ingrid J Apel, Tianlei Xu, Zhaohui Qin, Felix Y Feng, Irfan A Asangani
The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has been unsuccessful; however, identifying mediators of the EWS/ETS function could offer new therapeutic options. Here we describe the dependency of EWS/ETS-driven transcription upon chromatin reader BET bromdomain proteins and investigate the potential of BET inhibitors in treating EWS. EWS/FLI1 and EWS/ERG were found in a transcriptional complex with BRD4, and knockdown of BRD2/3/4 significantly impaired the oncogenic phenotype of EWS cells...
June 13, 2018: Cancer Research
Jian-Ping He, Pei-Pei Hou, Qi-Tao Chen, Wei-Jia Wang, Xiao-Yu Sun, Peng-Bo Yang, Ying-Ping Li, Lu-Ming Yao, Xiaotong Li, Xin-Dong Jiang, Kun-Yi Chien, Zhi-Ming Zhang, Qiu-Wan Wu, Allison J Cowin, Qiao Wu, Hang-Zi Chen
p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. FliI was highly expressed in clinical breast cancer samples, and heterozygous deletion of FliI retarded development of mammary tumors in PyVT mice...
June 13, 2018: Cancer Research
Jae Ho Seo, Ekta Agarwal, Kelly G Bryant, M Cecilia Caino, Eui Tae Kim, Andrew V Kossenkov, Hsin-Yao Tang, Lucia R Languino, Dmitry I Gabrilovich, Andrew R Cohen, David W Speicher, Dario C Altieri
Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain...
June 13, 2018: Cancer Research
Jingshan Tong, Xingnan Zheng, Xiao Tan, Rochelle Fletcher, Zaneta Nikolovska-Coleska, Jian Yu, Lin Zhang
Mcl-1, a pro-survival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anti-cancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. In this study, we show in colon cancer cells that histone deacetylase inhibitors (HDACi) induce GSK3β-dependent Mcl-1 phosphorylation, but not degradation or downregulation...
June 12, 2018: Cancer Research
Lei Wang, Sara J Felts, Virginia P Van Keulen, Adam D Scheid, Matthew S Block, Svetomir N Markovic, Larry R Pease, Yuji Zhang
Genome-wide identification and characterization of long non-coding RNAs (lncRNAs) in individual immune cell lineages helps us better understand the driving mechanisms behind melanoma and advance personalized patient treatment. To elucidate the transcriptional landscape in diverse immune cell types of peripheral blood cells (PBC) in stage IV melanoma, we used whole transcriptome RNA sequencing to profile lncRNAs in CD4+, CD8+, and CD14+ PBC from 132 patient samples. Our integrative computational approach identified 27,625 expressed lncRNAs, 2,744 of which were novel...
June 12, 2018: Cancer Research
Junchen Liu, Guo Chen, Zezhen Liu, Shaoyou Liu, Zhiduan Cai, Pan You, Yuepeng Ke, Li Lai, Yun Huang, Hongchang Gao, Liangcai Zhao, Helene Pelicano, Peng Huang, Wallace L McKeehan, Chin-Lee Wu, Cong Wang, Weide Zhong, Fen Wang
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. How it contributes to PCa progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here we report that FGFR1 tyrosine kinase reprograms the energy metabolism of PCa cells by regulating expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis...
June 11, 2018: Cancer Research
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