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Cancer Research

Michael Woolman, Claudia M Kuzan-Fischer, Isabelle Ferry, Taira Kiyota, Betty Luu, Megan Wu, David G Munoz, Sunit Das, Ahmed Aman, Michael David Taylor, James T Rutka, Howard Joeseph Ginsberg, Arash Zarrine-Afsar
Medulloblastoma (MB) is a pediatric malignant brain tumor comprised of four different subgroups (WNT, SHH, Group 3, Group 4), each of which are a unique biological entity with distinct clinico-pathological, molecular, and prognostic characteristics. While risk stratification of MB patients based on molecular features may offer personalized therapies, conventional subgroup identification methods take too long and are unable to deliver subgroup information intraoperatively. This limitation prevents subgroup-specific adjustment of the extent or the aggressiveness of the tumor resection by the neurosurgeon...
March 19, 2019: Cancer Research
Guizhong Zhang, Xin Li, Qian Chen, Junxin Li, Qingguo Ruan, Youhai H Chen, Xiaolu Yang, Xiaochun Wan
Epidermal growth factor receptor (EGFR) regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane...
March 19, 2019: Cancer Research
Jun Wang, Diana M Merino, Nicholas Light, Brian L Murphy, Yong-Dong Wang, Xiaohui Guo, Andrew P Hodges, Lianne Q Chau, Kun-Wei Liu, Girish Dhall, Shahab Asgharzadeh, Erin N Kiehna, Ryan J Shirey, Kim D Janda, Michael David Taylor, David Malkin, David W Ellison, Scott R VandenBerg, Charles G Eberhart, Rosalie C Sears, Martine F Roussel, Richard J Gilbertson, Robert J Wechsler-Reya
Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for CPC patients depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histological level, and like the hypodiploid subset of human CPC, exhibited multiple whole-chromosome losses, particularly of chromosomes 8, 12 and 19...
March 18, 2019: Cancer Research
Orla T Cox, Shelley J Edmunds, Katja Simon-Keller, Bo Li, Bruce Moran, Niamh E Buckley, Milan Bustamante-Garrido, Nollaig Healy, Ciara H O'Flanagan, William M Gallagher, Richard D Kennedy, René Bernards, Carlos Caldas, Suet-Feung Chin, Alexander Marx, Rosemary O'Connor
The PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an Epithelial-to-Mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of non-transformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer...
March 18, 2019: Cancer Research
Grazia Ambrosini, Catherine Do, Benjamin Tycko, Ronald B Realubit, Charles Karan, Elgilda Musi, Richard D Carvajal, Vivian Chua, Andrew E Aplin, Gary K Schwartz
Bromodomain and extra terminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here we evaluated the mechanisms of BETi resistance in uveal melanoma (UM), a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107, and RNA sequencing of BETi-resistant cells...
March 18, 2019: Cancer Research
Shili Xu, Tianyuan Zhou, Hanna M Doh, K Ryan Trinh, Art Catapang, Jason T Lee, Daniel Braas, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua P Sasine, John M Timmerman, Sarah M Larson, Youngsoo Kim, A Robert Macleod, Sherie L Morrison, Harvey R Herschman
Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many co-express HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1-HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma (MM) cell lines are HK1-HK2+...
March 18, 2019: Cancer Research
Shih-Han Kao, Wei-Chung Cheng, Yi-Ting Wang, Han-Tsang Wu, Han-Yu Yeh, Yu-Ju Chen, Ming-Hsui Tsai, Kou-Juey Wu
Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a co-factor of the Drosha-DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities...
March 15, 2019: Cancer Research
Raymond B Birge, Canan Kasikara, Viralkumar Davra, David Calianese, Ke Geng, Thomas E Spires, Michael Quigley, Michael Wichroski, Ganapathy Sriram, Lucia Suarez-Lopez, Michael B Yaffe, Sergei V Kotenko, Mariana S De Lorenzo
Tyro3, Axl, and Mertk (abbreviated TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS->TAM receptor->PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance...
March 15, 2019: Cancer Research
Konstantinos Zormpas-Petridis, Neil P Jerome, Matthew David Blackledge, Fernando Carceller, Evon Poon, Matthew Clarke, Ciara M McErlean, Giuseppe Barone, Alexander Koers, Sucheta J Vaidya, Lynley V Marshall, Andrew D J Pearson, Lucas Moreno, John Anderson, Neil Sebire, Kieran McHugh, Dow-Mu Koh, Yinyin Yuan, Louis Chesler, Simon P Robinson, Yann Jamin
Childhood neuroblastoma is a hypervascular tumor of neural origin for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe a MRI-pathological cross-correlative approach using intrinsic susceptibility (IS-) and susceptibility contrast (SC-) MRI to non-invasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib...
March 15, 2019: Cancer Research
Bryson William Katona, Rebecca A Glynn, Kayla E Paulosky, Zijie Feng, Caroline I Davis, Jian Ma, Corbett T Berry, Katherine M Szigety, Smita Matkar, Yuanyuan Liu, Haoren Wang, Yuan Wu, Xin He, Bruce D Freedman, Donita C Brady, Xianxin Hua
Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer (CRC), however, remains unclear. Here we demonstrate that menin was overexpressed in CRC and that inhibition of menin synergized with small molecule inhibitors of EGFR (iEGFR) to suppress CRC cells and tumor xenografts in vivo in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for CRC growth, and promoted its expression...
March 15, 2019: Cancer Research
Tatiana Shorstova, Maud Marques, Jie Su, Jake Johnston, Claudia L Kleinman, Nancy Hamel, Sidong Huang, Moulay A Alaoui-Jamali, William D Foulkes, Michael Witcher
The antitumor activity of bromodomain and extra-terminal motif protein inhibitors (BETi) has been demonstrated across numerous types of cancer. As such, these inhibitors are currently undergoing widespread clinical evaluation. However, predictive biomarkers allowing the stratification of tumors into responders and non-responders to BETi are lacking. Here we showed significant anti-proliferative effects of low dosage BETi in vitro and in vivo against aggressive ovarian and lung cancer models lacking SMARCA4 and SMARCA2, key components of SWI/SNF chromatin remodeling complexes...
March 15, 2019: Cancer Research
Laura Simone, Francesco Pisani, Maria Grazia Mola, Manuela De Bellis, Giuseppe Merla, Lucia Micale, Antonio Frigeri, Angelo Luigi Vescovi, Maria Svelto, Grazia P Nicchia
The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis...
March 15, 2019: Cancer Research
Mary Hoffman, Aaron Gillmor, Daniel J Kunz, Michael J Johnston, Ana Nikolic, Kiran Narta, Mehdi Zarrei, Jennifer C King, Katrina Ellestad, Ngoc Ha Dang, Florence M G Cavalli, Michelle Kushida, Fiona J Coutinho, Yuankun Zhu, Betty Luu, Yussanne Ma, Andrew J Mungall, Richard A Moore, Marco A Marra, Michael David Taylor, Trevor J Pugh, Peter B Dirks, Douglas Strother, Lucie Lafay-Cousin, Adam C Resnick, Stephen W Scherer, Donna L Senger, Benjamin D Simons, Jennifer A Chan, A Sorana Morrissy, Marco Gallo
Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of non-synonymous single nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole genome datasets for two patients and their parents...
March 15, 2019: Cancer Research
Ernesto Diaz-Flores, Evan Q Comeaux, Kailyn L Kim, Ella M Melnik, Kyle Beckman, Kara L Davis, Kevin Wu, Jon Akutagawa, Olga Bridges, Roberta Marino, Margo Wohlfeil, Benjamin S Braun, Charles G Mullighan, Mignon L Loh
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of acute lymphoblastic leukemia (ALL), including hypodiploid B cell ALL for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL...
March 12, 2019: Cancer Research
Ran Tao, Najiba Murad, Zhenhua Xu, Peng Zhang, Konstantin Okonechnikov, Marcel Kool, Samuel Rivero-Hinojosa, Christopher Lazarski, Pan Zheng, Yang Liu, Charles G Eberhart, Brian R Rood, Roger Packer, Yanxin Pei
A subset of Group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human Group 3 medulloblastoma based on histology and gene expression profiling. Gene expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA)...
March 12, 2019: Cancer Research
Aling Shen, Youqin Chen, Liya Liu, Yue Huang, Hongwei Chen, Fei Qi, Jiumao Lin, Zhiqing Shen, Xiangyan Wu, Meizhu Wu, Qiongyu Li, Liman Qiu, Na Yu, Thomas J Sferra, Jun Peng
The RNA-binding protein PNO1 is critical for ribosome biogenesis, but its potential role in cancer remains unknown. In the present study, on-line data mining, cDNA and tissue microarrays indicated that PNO1 expression was higher in colorectal cancer (CRC) tissue than in noncancerous tissue, and its overexpression was associated with worse patient survival. Gain-of-function and loss-of-function studies demonstrated that PNO1 knockdown suppressed growth of CRC cells in vitro and in vivo, while PNO1 overexpression promoted CRC cell proliferation in vitro...
March 12, 2019: Cancer Research
Zeynep Madak-Erdogan, Shoham Band, Yiru Chen Zhao, Brandi Patrice Smith, Eylem Kulkoyluoglu-Cotul, Qianying Zuo, Ashlie Santaliz Casiano, Kinga Wrobel, Gianluigi Rossi, Rebecca Lee Smith, Sung Hoon Kim, John A Katzenellenbogen, Mariah L Johnson, Meera Patel, Natascia Marino, Anna Maria V Storniolo, Jodi A Flaws
Obesity is a risk factor for postmenopausal estrogen receptor alpha positive (ER(+)) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese vs. non-obese postmenopausal women...
March 12, 2019: Cancer Research
Gregory D Longmore, Priscilla Y Hwang, Audrey Brenot, Steven C George, Ashley C King
Collective cell migration is an adaptive, coordinated interactive process involving cell-cell and cell-extracellular matrix (ECM) microenvironmental interactions. A critical aspect of collective migration is the sensing and establishment of directional movement. It has been proposed that a subgroup of cells known as leader cells localize at the front edge of a collectively migrating cluster and are responsible for directing migration. However, it is unknown how and when leader cells arrive at the front edge and what environmental cues dictate leader cell development and behavior...
March 12, 2019: Cancer Research
Suchitra Natarajan, Kaitlyn M Foreman, Michaela I Soriano, Ninna S Rossen, Hussein Shehade, Daniel R Fregoso, Joshua T Eggold, Venkatesh Krishnan, Oliver Dorigo, Adam J Krieg, Sarah C Heilshorn, Subarna Sinha, Katherine C Fuh, Erinn B Rankin
Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here we report that the HGSOC tumor-mesothelial niche was hypoxic and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion...
March 12, 2019: Cancer Research
Fiona Henderson, Hannah R Johnston, Andrew P Badrock, Emrys A Jones, Duncan Forster, Raghavendar Thyagaraja Nagaraju, Christos Evangelou, Jivko Kamarashev, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria Ramirez, Shuning He, B Ewa Snaar-Jagalska, Katherine Hollywood, Warwick B Dunn, Herman P Spaink, Michael P Smith, Paul Lorigan, Emmanuelle Claude, Kaye J Williams, Adam W McMahon, Adam Hurlstone
Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined positron emission tomography (PET), desorption electrospray ionisation-mass spectrometry (DESI-MS), non-imaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis...
March 12, 2019: Cancer Research
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