Cancer Research

Christopher Gromisch, Motaz Qadan, Mariana Albuquerque Machado, Kebin Liu, Yolonda Colson, Mark W Grinstaff
This review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease...
March 27, 2020: Cancer Research
Hong Zhu, Fangjie Yan, Tao Yuan, Meijia Qian, Tianyi Zhou, Xiaoyang Dai, Ji Cao, Meidan Ying, Xiaowu Dong, Qiaojun He, Bo Yang
Yes-associated protein (YAP) and its paralogue, transcriptional co-activator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in HCC remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in HCC models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB...
March 26, 2020: Cancer Research
Gianluca Selvaggio, Sara Canato, Archana Pawar, Pedro T Monteiro, Patrícia S Guerreiro, M Manuela Brás, Florence Janody, Claudine Chaouiya
Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes...
March 26, 2020: Cancer Research
Chi Hin Wong, Ut Kei Lou, Youjia Li, Stephen L Chan, Joanna H M Tong, Ka-Fai To, Yangchao Chen
The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared to non-tumor human pancreatic ductal epithelial (HPDE) cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63 % of primary tumors (53 out of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell cycle progression and apoptosis...
March 26, 2020: Cancer Research
John J Krais, Yifan Wang, Andrea J Bernhardy, Emma Clausen, Jessica A Miller, Kathy Q Cai, Clare L Scott, Neil Johnson
BRCA1 gene mutations impair homologous recombination (HR) DNA repair, resulting in cellular senescence and embryonic lethality in mice. Therefore, BRCA1-deficient cancers require adaptations that prevent excessive genomic alterations from triggering cell death. RNF168-mediated ubiquitination of γH2AX at K13/15 (ub-H2AX) serves as a recruitment module for the localization of 53BP1 to DNA break sites. Here, we found multiple BRCA1 mutant cancer cell lines and primary tumors with low levels of RNF168 protein expression...
March 25, 2020: Cancer Research
Lianliang Liu, Rong Jin, Jiaqing Hao, Jun Zeng, Di Yin, Yanmei Yi, Mingming Zhu, Anita Mandal, Yuan Hua, Chin K Ng, Nejat K Egilmez, Edward R Sauter, Bing Li
Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in pro-tumor macrophages...
March 25, 2020: Cancer Research
Yuichi Mitobe, Kaori Iino, Ken-Ichi Takayama, Kazuhiro Ikeda, Takashi Suzuki, Kenjiro Aogi, Hidetaka Kawabata, Yutaka Suzuki, Kuniko Horie-Inoue, Satoshi Inoue
Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of ER-positive breast cancer patients by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in ER-positive breast cancer patients...
March 25, 2020: Cancer Research
Marco Bruschi, Laure Garnier, Elouan Cleroux, Alicia Giordano, Michael Dumas, Anaïs F Bardet, Thomas Kergrohen, Stanislas Quesada, Pierre Cesses, Michael Weber, François Gerbe, Philippe Jay
Colorectal cancer (CRC) initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of CRC development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by Apc inactivation in intestinal crypts. Hyper-activation of the Wnt pathway via Apc inactivation in crypt base columnar (CBC) intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation...
March 25, 2020: Cancer Research
Ian A Prior, Fiona E Hood, James L Hartley
Ras is frequently mutated in cancer; however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. In order to provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types...
March 24, 2020: Cancer Research
Yi Zhao, Neha Kaushik, Jae-Hyeok Kang, Nagendra Kumar Kaushik, Seung Han Son, Nizam Uddin, Min-Jung Kim, Chul Geun Kim, Su-Jae Lee
Stemness and epithelial-mesenchymal transition (EMT) are two fundamental characteristics of metastasis that are controlled by diverse regulatory factors, including transcription factors. Compared with other subtypes of breast cancer, basal-type or triple-negative breast cancer (TNBC) have high frequencies of tumor relapse. However, the role of alpha-globin transcription factor CP2 (TFCP2) has not been reported as an oncogenic driver in those breast cancers. Here we show that TFCP2 is a potent factor essential for EMT, stemness, and metastasis in breast cancer...
March 19, 2020: Cancer Research
Dezhong Lv, Kang Xu, Xiyun Jin, Junyi Li, Yunchen Shi, Mengying Zhang, Xiaoyan Jin, Yongsheng Li, Juan Xu, Xia Li
Long noncoding RNAs (LncRNA) play important roles in maintaining morphology and function of tissues, and their regulatory effectiveness is closely associated with spatial expression. To provide a comprehensive spatial atlas of expression for lncRNA, we propose LncSpA ( to explore tissue-elevated (TE) lncRNA across human normal and adult and pediatric cancer tissues. In total, 71,131 and 12,007 TE lncRNA and 634 clinical-related TE lncRNA were identified across 38 normal and 33 adult cancer tissues...
March 19, 2020: Cancer Research
Jacqueline H Starrett, Alexis A Guernet, Maria Emanuela Cuomo, Kamrine E Poels, Iris K van Alderwerelt van Rosenburgh, Amy Nagelberg, Dylan Farnsworth, Kristin S Price, Hina Khan, Kumar Dilip Ashtekar, Mmaserame Gaefele, Deborah Ayeni, Tyler F Stewart, Alexandra Kuhlmann, Susan Kaech, Arun M Unni, Robert Homer, William W Lockwood, Franziska Michor, Sarah B Goldberg, Mark A Lemmon, Paul D Smith, Darren Ae Cross, Katerina Politi
Osimertinib, a mutant-specific third generation EGFR TKI, is emerging as the preferred first-line therapy for EGFR mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R-induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR - either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation...
March 19, 2020: Cancer Research
Yi Hu, Huimin Liu, Chuanfeng Fang, Chen Li, Fjorela Xhyliu, Hayley Dysert, Juraj Bodo, Gabriel Habermehl, Benjamin E Russell, Wenjun Li, Marcia Chappell, Xiaofeng Jiang, Sarah L Ondrejka, Eric D Hsi, Jaroslaw P Maciejewski, Qing Yi, Kenneth C Anderson, Nikhil C Munshi, Geyou Ao, Jason N Valent, Jianhong Lin, Jianjun Zhao
Multiple myeloma (MM) is an incurable refractory hematological malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in MM and tested single-wall carbon nanotube delivery of miR-26a in vitro and in vivo. miR-26a was downregulated in patient MM cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in MM cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using Stable isotope labeling by amino acids in cell culture (SILAC) medium followed by mass spectrometry analysis...
March 19, 2020: Cancer Research
Jaebeom Cho, Hyo-Jong Lee, Su Jung Hwang, Hye-Young Min, Han Na Kang, A-Young Park, Seung Yeob Hyun, Jeong Yeon Sim, Ho Jin Lee, Hyun-Ji Jang, Young-Ah Suh, Sungyoul Hong, Young Kee Shin, Hye Ryun Kim, Ho-Young Lee
Quiescent cancer cells are believed to cause cancer progression after chemotherapy through unknown mechanisms. We show here that human non-small-cell lung cancer (NSCLC) cell line-derived, quiescent-like, slow-cycling cancer cells (SCC) and residual patient-derived xenograft (PDX) tumors after chemotherapy experience activating transcription factor 6 (ATF6)-mediated upregulation of various cytokines, which acts in a paracrine manner to recruit fibroblasts. Cancer-associated fibroblasts (CAF) underwent transcriptional upregulation of COX2 and type I collagen (Col-I), which subsequently triggered a slow-to-active-cycling switch in SCC through prostaglandin E2 (PGE2)- and integrin/Src-mediated signaling pathways, leading to cancer progression...
March 19, 2020: Cancer Research
Casimiro Gerarduzzi, Ursula Hartmann, Andrew Leask, Elliot Drobetsky
The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCPs) are secreted into the ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins and cell-matrix interactions to influence normal cellular functions. In the tumor microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can support multiple hallmarks of carcinogenesis by interacting with various cellular components that are coupled to an array of downstream signals...
March 19, 2020: Cancer Research
Koen D Flach, Manikandan Periyasamy, Ajit Jadhav, Dorjbal Dorjsuren, Joseph C Siefert, Theresa E Hickey, Mark Opdam, Hetal Patel, Sander Canisius, David M Wilson, Maria Donaldson Collier, Stefan Prekovic, Marja Nieuwland, Roelof Jc Kluin, Alexey V Zakharov, Jelle Wesseling, Lodewyk F A Wessels, Sabine C Linn, Wayne D Tilley, Anton Simeonov, Simak Ali, Wilbert Zwart
Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex...
March 19, 2020: Cancer Research
Man-Li Luo, Fang Zheng, Wenying Chen, Zhi-Mei Liang, Gurushankar Chandramouly, Jianan Tan, Nicholas A Willis, Chun-Hau Chen, Mateus de Oliveira Taveira, Xiao Zhen Zhou, Kun Ping Lu, Ralph Scully, Gerburg M Wulf, Hai Hu
PARP inhibitor monotherapies effectively treat breast, ovary, prostate, and pancreatic cancer patients with BRCA1 mutations, but not the more frequent BRCA-wildtype cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we report here that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by post-phosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, which is catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells...
March 19, 2020: Cancer Research
Jianjiang Xie, Jianheng Ye, Zhiduan Cai, Yong Luo, Xuejin Zhu, Yulin Deng, Yuanfa Feng, Yingke Liang, Ren Liu, Zhaodong Han, Yuxiang Liang, Yu Zheng, Rujun Mo, Yangjia Zhuo, Yongding Wu, Funeng Jiang, Jianguo Zhu, Chin-Lee Wu, Weide Zhong
Metformin is an oral drug widely used for the treatment of type 2 diabetes mellitus. Numerous studies have demonstrated the value of metformin in cancer treatment. However, for metformin to elicit effects on cancer this often requires a high dosage, and any underlying mechanism for how to improve its inhibitory effects remains unknown. Here we found that low mRNA expression of glycerol-3-phosphate dehydrogenase 1 (GPD1) may predict a poor response to metformin treatment in 15 cancer cell lines. In vitro and in vivo, metformin treatment alone significantly suppressed cancer cell proliferation, a phenotype enhanced by GPD1 overexpression...
March 16, 2020: Cancer Research
Christophe A Girard, Margaux Lecacheur, Rania Ben Jouira, Ilona Berestjuk, Serena Diazzi, Virginie Prod'homme, Aude Mallavialle, Frédéric Larbret, Maéva Gesson, Sébastien Schaub, Sabrina Pisano, Stéphane Audebert, Bernard Mari, Cédric Gaggioli, Eleonora Leucci, Jean-Christophe Marine, Marcel Deckert, Sophie Tartare-Deckert
Aberrant extracellular matrix (ECM) deposition and stiffening is a physical hallmark of several solid cancers and is associated with therapy failure. BRAF-mutant melanomas treated with BRAF and MEK inhibitors almost invariably develop resistance that is frequently associated with transcriptional reprogramming and a de-differentiated cell state. Melanoma cells secrete their own ECM proteins, an event that is promoted by oncogenic BRAF inhibition. Yet, the contribution of cancer cell-derived ECM and tumor mechanics to drug adaptation and therapy resistance remains poorly understood...
March 16, 2020: Cancer Research
Maria Teresa Majorini, Valeria Cancila, Alice Rigoni, Laura Botti, Matteo Dugo, Tiziana Triulzi, Loris De Cecco, Enrico Fontanella, Elena Jachetti, Elda Tagliabue, Claudia Chiodoni, Claudio Tripodo, Mario P Colombo, Daniele Lecis
Tumor growth and development is determined by both cancer cell-autonomous and microenvironmental mechanisms, including the contribution of infiltrating immune cells. Since the role of mast cells (MC) in this process is poorly characterized and even controversial, we investigated their part in breast cancer (BC). Crossing C57BL/6 MMTV-PyMT mice, which spontaneously develop mammary carcinomas, with MC-deficient C57BL/6-KitW-sh/W-sh (Wsh) mice, showed that MC promote tumor growth and prevent the development of basal CK5-positive areas in favor of a luminal gene program...
March 16, 2020: Cancer Research
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