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Bharti Garg, Bhuwan Giri, Shrey Modi, Vrishketan Sethi, Iris Castro, Oliver Umland, Yuguang Ban, Shweta Lavania, Rajinder Dawra, Sulagna Banerjee, Selwyn Vickers, Nipun B Merchant, Steven Xi Chen, Eli Gilboa, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja
BACKGROUND & AIMS: Immunotherapies are ineffective against pancreatic cancer. We investigated whether the activity of nuclear factor (NF)κB in pancreatic stromal cells contributes to an environment that suppresses anti-tumor immune response. METHODS: Pancreata of C57BL/6 or Rag1-/- mice were given pancreatic injections of a combination of KrasG12D/+; Trp53 R172H/+; Pdx-1cre (KPC) pancreatic cancer cells and pancreatic stellate cells (PSCs) extracted from C57BL/6 (control) or mice with disruption of the gene encoding the NFkB p50 subunit (Nfkb1 or p50-/- mice)...
June 14, 2018: Gastroenterology
Catherine J Libby, Sixue Zhang, Gloria A Benavides, Sarah E Scott, Yanjie Li, Matthew Redmann, Anh Nhat Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Corinne Elizabeth Augelli-Szafran, Wei Zhang, Anita B Hjelmeland
Tumor heterogeneity has hampered the development of novel effective therapeutic options for aggressive cancers, including the deadly primary adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is partially attributed to the tumor initiating cell (TIC) subset that contains highly tumorigenic, stem-like cells. TICs display metabolic plasticity but can have a reliance on aerobic glycolysis. Elevated expression of GLUT1 and GLUT3 is present in many cancer types, with GLUT3 being preferentially expressed in brain TICs (BTICs) to increase survival in low nutrient tumor microenvironments, leading to tumor maintenance...
June 15, 2018: ACS Chemical Biology
Matthew Dankner, Mathieu Lajoie, Dan Moldoveanu, Tan-Trieu Nguyen, Paul Savage, Shivshankari Rajkumar, Xiu Huang, Maria Lvova, Alexei Protopopov, Dana Vuzman, David Hogg, Morag Park, Marie-Christine Guiot, Kevin Petrecca, Catalin Mihalcioiu, Ian R Watson, Peter M Siegel, April A N Rose
PURPOSE: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. EXPERIMENTAL DESIGN: Tumors from patients with BRAF WT, V600E (class I) and L597S (class II) metastatic melanoma were used to generate patient-derived-xenografts (PDX)...
June 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
Eliza Li Shan Fong, Tan Boon Toh, Quy Xiao Xuan Lin, Zheng Liu, Lissa Hooi, Masturah Bte Mohd Abdul Rashid, Touati Benoukraf, Edward Kai-Hua Chow, The Hung Huynh, Hanry Yu
This data article presents datasets associated with the research article entitled "Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer" (Fong et al., 2018) [1]. A three-dimensional macroporous sponge system was used to generate in vitro counterparts to various hepatocellular carcinoma patient-derived xenograft (HCC-PDX) lines. This article describes the viability, proliferative capacity and molecular features (genomic and transcriptomic profiles) of the cultured HCC-PDX cells...
June 2018: Data in Brief
Gulam M Rather, Siang-Yo Lin, Hongxia Lin, Whitney Banach-Petrosky, Kim M Hirshfield, Chen-Yong Lin, Michael D Johnson, Zoltan Szekely, Joseph R Bertino
The antitumor effects of a novel antibody drug conjugate (ADC) was tested against human solid tumor cell lines and against human triple negative breast cancer (TNBC) xenografts in immunosuppressed mice. The ADC targeting activated matriptase of tumor cells was synthesized by using the potent anti-tubulin toxin, monomethyl auristatin-E linked to the activated matriptase-specific monoclonal antibody (M69) via a lysosomal protease-cleavable dipeptide linker. This ADC was found to be cytotoxic against multiple activated matriptase-positive epithelial carcinoma cell lines in vitro and markedly inhibited growth of triple negative breast cancer xenografts and a primary human TNBC (PDX) in vivo ...
May 25, 2018: Oncotarget
David S Hersh, Bryan G Harder, Alison Roos, Sen Peng, Jonathan E Heath, Teklu Legesse, Anthony J Kim, Graeme F Woodworth, Nhan L Tran, Jeffrey A Winkles
Background: Glioblastoma (GBM) is a difficult-to-treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy-resistant. Our prior work has demonstrated an important role for the TWEAK receptor Fn14 in GBM patho-biology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. Methods: Fn14 mRNA expression levels in the non-neoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from the TCGA data portal...
April 20, 2018: Neuro-oncology
Jeff Hirst, Harsh B Pathak, Stephen Hyter, Ziyan Y Pessetto, Thuc Ly, Stefan Graw, Devin C Koestler, Adam J Krieg, Katherine F Roby, Andrew K Godwin
Drug development for front-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anti-cancer drugs...
June 11, 2018: Cancer Research
Yann Wallez, Charles R Dunlop, Timothy Isaac Johnson, Siang-Boon Koh, Chiara Fornari, James Wt Yates, Sandra Bernaldo de Quirós Fernández, Alan Lau, Frances M Richards, Duncan I Jodrell
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard-of-care, but shows very limited anti-tumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response (DDR), plays a central role in safeguarding cells from replication stress (RS) and can therefore limit the efficacy of antimetabolite drug therapies...
June 11, 2018: Molecular Cancer Therapeutics
Olivia M Yu, Jorge A Benitez, Steven W Plouffe, Daniel Ryback, Andrea Klein, Jeff Smith, Jason Greenbaum, Benjamin Delatte, Anjana Rao, Kun-Liang Guan, Frank B Furnari, Olga Meiri Chaim, Shigeki Miyamoto, Joan Heller Brown
The role of YAP (Yes-associated protein 1) and MRTF-A (myocardin-related transcription factor A), two transcriptional co-activators regulated downstream of GPCRs (G protein-coupled receptors) and RhoA, in the growth of glioblastoma cells and in vivo glioblastoma multiforme (GBM) tumor development was explored using human glioblastoma cell lines and tumor-initiating cells derived from patient-derived xenografts (PDX). Knockdown of these co-activators in GSC-23 PDX cells using short hairpin RNA significantly attenuated in vitro self-renewal capability assessed by limiting dilution, oncogene expression, and neurosphere formation...
June 11, 2018: Oncogene
Tao Wang, Rong Lu, Payal Kapur, Bijay S Jaiswal, Raquibul Hannan, Ze Zhang, Ivan Pedrosa, Jason J Luke, He Zhang, Leonard D Goldstein, Qurratulain Yousuf, Yi-Feng Gu, Tiffani McKenzie, Allison Joyce, Min S Kim, Xinlei Wang, Danni Luo, Oreoluwa Onabolu, Christina Stevens, Zhiqun Xie, Mingyi Chen, Alexander Filatenkov, Jose Torrealba, Xin Luo, Wenbin Guo, Jingxuan He, Eric Stawiski, Zora Modrusan, Steffen Durinck, Somasekar Seshagiri, James Brugarolas
By leveraging tumorgraft (PDX) RNA-Seq data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in Renal Cell Carcinoma (RCC), and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for Tregs, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells...
June 8, 2018: Cancer Discovery
Joseph Candiello, Taraka Sai Pavan Grandhi, Saik Kia Goh, Vimal Vaidya, Maya Lemmon-Kishi, Kiarash Rahmani Eliato, Robert Ros, Prashant N Kumta, Kaushal Rege, Ipsita Banerjee
Organoids, which exhibit spontaneous organ specific organization, function, and multi-cellular complexity, are in essence the in vitro reproduction of specific in vivo organ systems. Recent work has demonstrated human pluripotent stem cells (hPSCs) as a viable regenerative cell source for tissue-specific organoid engineering. This is especially relevant for engineering islet organoids, due to the recent advances in generating functional beta-like cells from human pluripotent stem cells. In this study, we report specific engineering of regenerative islet organoids of precise size and cellular heterogeneity, using a novel hydrogel system, Amikagel...
May 25, 2018: Biomaterials
Hongwei Lv, Changzheng Wang, Tian Fang, Ting Li, Guishuai Lv, Qin Han, Wen Yang, Hongyang Wang
Vitamin C (L-ascorbic acid, ascorbate, VC) is a potential chemotherapeutic agent for cancer patients. However, the anti-tumor effects of pharmacologic VC on hepatocellular carcinoma (HCC) and liver cancer stem cells (CSCs) remain to be fully elucidated. Panels of human HCC cell lines as well as HCC patient-derived xenograft (PDX) models were employed to investigate the anti-tumor effects of pharmacologic VC. The use of VC and the risk of HCC recurrence were examined retrospectively in 613 HCC patients who received curative liver resection as their initial treatment...
2018: NPJ precision oncology
Federica Guffanti, Maddalena Fratelli, Monica Ganzinelli, Marco Bolis, Francesca Ricci, Francesca Bizzaro, Rosaria Chilà, Federica Paola Sina, Robert Fruscio, Michela Lupia, Ugo Cavallaro, Maria Rosa Cappelletti, Daniele Generali, Raffaella Giavazzi, Giovanna Damia
A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanconi anemia, homologous recombination, base excision repair, mismatch repair and translesion repair pathways and the methylation patterns of some of these genes. We also investigated the correlation with the response to platinum-based therapy...
May 15, 2018: Oncotarget
Li-Dong Zu, Xing-Chun Peng, Zhi Zeng, Jing-Long Wang, Li-Li Meng, Wei-Wei Shen, Chun-Ting Hu, Ye Yang, Guo-Hui Fu
BACKGROUND: To test the hypothesis that activated extracellular signal-regulated kinase (ERK) regulates P65-miR23a/27a/24 axis in gastric cancer (GC) and the ERK-P65-miR23a/27a/24 axis plays an important role in the development of GC, and to evaluate the role of gastrin in GC progression and ERK-P65-miR23a/27a/24 axis. METHODS: The component levels of the ERK-P65-miR23a/27a/24 axis in four fresh GC tissues, 101 paraffin-embedded GC tissues and four GC cell lines were determined by Western blotting, immunohistochemistry (IHC) or qRT-PCR...
June 4, 2018: Journal of Experimental & Clinical Cancer Research: CR
Amanda Lo Van, Nobuyuki Sakayori, Mayssa Hachem, Mounir Belkouch, Madeleine Picq, Baptiste Fourmaux, Michel Lagarde, Noriko Osumi, Nathalie Bernoud-Hubac
Docosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA) that is required for proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases, a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with aging or neurodegenerative diseases. In this context, targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases...
June 1, 2018: Molecular Neurobiology
Mian Xie, Shenhai Wei, Xiaojun Wu, Xiaoxiang Li, You You, Chaosheng He
INTRODUCTION: Adenoid cystic carcinoma (ACC) of the trachea lacks of well-characterized molecular markers. There is currently no specific treatment for metastatic ACC of the trachea. This study aimed to identify genomic mutations of Notch pathway and investigate the efficacy of NOTCH inhibitor in ACC of the trachea. METHODS: 73 Patients with ACC of the trachea at four institutions from 2008 to 2016 were identified. Analysis of hotspot mutations in cancer-related genes of Notch pathway was performed using next generation sequencing...
July 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Ashley N Gilbert, Joshua C Anderson, Christine W Duarte, Rachael S Shevin, Catherine P Langford, Raj Singh, G Yancey Gillespie, Christopher D Willey
Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing...
May 30, 2018: Scientific Reports
Shilpa Bhatia, Jaspreet Sharma, Sanjana Bukkapatnam, Ayman Oweida, Shelby Lennon, Andy V Phan, Dallin Milner, Nomin Uyanga, Antonio Jimeno, David Raben, Hilary Somerset, Lynn Heasley, Sana D Karam
PURPOSE: The clinical success of targeted therapies such as cetuximab and radiation (RT) is hampered by the low response rates and development of therapeutic resistance. In the current study, we investigated the involvement of EphB4-ephrin-B2 pro-tumorigenic signaling in mediating resistance to EGFR inhibition and radiation therapy in head and neck cancers. EXPERIMENTAL DESIGN: We used patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines to test our hypothesis...
May 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rieko Oyama, Mami Takahashi, Fusako Kito, Marimu Sakumoto, Kumiko Shiozawa, Zhiwei Qiao, Akihiko Yoshida, Makoto Endo, Akira Kawai, Tadashi Kondo
Primary leiomyosarcoma (LMS) of bone is a rare and aggressive mesenchymal malignancy that differentiates toward smooth muscle. Complete resection is the only curable treatment, and novel therapeutic approaches for primary LMS of bone have long been desired. Patient-derived xenografts (PDXs) and cell lines are invaluable tools for preclinical studies. Here, we established PDXs from a patient with primary LMS of bone and a cell line from an established PDX. Bone primary LMS tissue was subcutaneously implanted into highly immune-deficient mice...
May 29, 2018: In Vitro Cellular & Developmental Biology. Animal
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