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Cancer Research

Mitsunobu Takeda, Jun Koseki, Hidekazu Takahashi, Norikatsu Miyoshi, Naohiro Nishida, Junichi Nishimura, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori, Naotsugu Haraguchi
Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSC remains a promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSC and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an anti-malarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug...
February 14, 2019: Cancer Research
Sharon A Tooze, Maria New, Tim Van Acker, Jun-Ichi Sakamaki, Ming Jiang, Rebecca E Saunders, Jaclyn Long, Victoria M-Y Wang, Axel Behrens, Padhmanand Sudhakar, Tamas Korcsmaros, Kevin M Ryan, Michael Howell, Joana Cerveira, Harold B J Jefferies
Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival...
February 14, 2019: Cancer Research
Rahul Kumar, Tariq A Bhat, Elise M Walsh, Ajay K Chaudhary, Jordan O'Malley, Johng S Rhim, Jianmin Wang, Carl D Morrison, Kristopher Attwood, Wiam Bshara, James L Mohler, Neelu Yadav, Dhyan Chandra
Although African-American (AA) prostate cancer (PCa) patients tend to develop greater therapeutic resistance and faster PCa recurrence compared to Caucasian-American men, the molecular mechanisms of this racial PCa disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c (CC) deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and PCa aggressiveness in AA men...
February 14, 2019: Cancer Research
Erica W Cloer, Dennis Goldfarb, Travis P Schrank, Bernard E Weissman, Michael B Major
The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across 226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo- and radioresistance...
February 13, 2019: Cancer Research
Levon M Khachigian
RNA-cleaving deoxyribozymes (DNAzymes) are synthetic single-stranded DNA-based catalytic molecules that can be engineered to bind to and cleave target mRNA at predetermined sites. These have been used as therapeutic agents in a range of preclinical cancer models and have entered clinical trials in Europe, China, and Australia. This review surveys regulatory insights into mechanisms of disease brought about by use of catalytic DNA in vitro and in vivo , including recent uses as nanosensors, nanoflowers, and nanosponges, and the emerging role of adaptive immunity underlying DNAzyme inhibition of cancer growth...
February 13, 2019: Cancer Research
Sandi A Kwee, Maarit Tiirikainen, Miles M Sato, Jared D Acoba, Runmin Wei, Wei Jia, Loic Le Marchand, Linda L Wong
Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). PET/CT has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by tissue uptake of the radiopharmaceutical 18F-flurocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent 18F-fluorocholine PET/CT followed by tumor resection and gene expression profiling...
February 13, 2019: Cancer Research
Alan R Gilmore, Matthew Alderdice, Kienan I Savage, Paul G O'Reilly, Aideen C Roddy, Philip D Dunne, Mark Lawler, Simon S McDade, David J Waugh, Darragh G McArt
Modern methods of acquiring molecular data have improved rapidly in recent years, making it easier for researchers to collect large volumes of information. However, this has increased the challenge of recognizing interesting patterns within the data. Atlas Correlation Explorer (ACE) is a user-friendly workbench for seeking associations between attributes in the cancer genome atlas (TCGA) database. It allows any combination of clinical and genomic data streams to be searched using an evolutionary algorithm approach...
February 13, 2019: Cancer Research
Jingxia Han, Jing Meng, Xiaorui Wang, Shan Yin, Qiang Zhang, Huijuan Liu, Rong Qin, Zhongwei Li, Weilong Zhong, Chao Zhang, Heng Zhang, Yuanhao Tang, Tingting Lin, Wanfeng Gao, Xiaoyun Zhang, Lan Yang, Yanrong Liu, Hong-Gang Zhou, Shuang Chen, Tao Sun, Cheng Yang
Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex...
February 13, 2019: Cancer Research
Thomas E Rohan, Tao Wang, Sheila Weinmann, Yihong Wang, Juan Lin, Mindy Ginsberg, Olivier Loudig
Dysregulation of microRNA (miRNA) expression may influence breast cancer progression, and experimental evidence suggests that miRNA silencing might suppress breast cancer metastasis. However, the relationship between miRNA and metastasis must be confirmed before this approach can be applied in the clinic. To this end, we conducted a 2-stage study in a cohort of 3760 breast cancer patients to first identify and then validate the association between miRNA expression and risk of distant metastasis. The first stage (discovery) entailed miRNA sequencing of 126 case-control pairs; qPCR was used to validate the findings in a separate set of 80 case-control pairs...
February 13, 2019: Cancer Research
Nazanin Rohani, Liangliang Hao, Maria S Alexis, Brian A Joughin, Konstantin Krismer, Mira N Moufarrej, Anthony R Soltis, Douglas A Lauffenburger, Michael B Yaffe, Christopher B Burge, Sangeeta N Bhatia, Frank B Gertler
Acidosis is a fundamental feature of the tumor microenvironment that directly regulates tumor cell invasion by affecting immune cell function, clonal cell evolution, and drug resistance. Despite the important association of tumor microenvironment acidosis with tumor cell invasion, relatively little is known regarding which areas within a tumor are acidic and how acidosis influences gene expression to promote invasion. Here we injected a labeled pH-responsive peptide to mark acidic regions within tumors. Surprisingly, acidic regions were not restricted to hypoxic areas and overlapped with highly proliferative, invasive regions at the tumor-stroma interface, which were marked by increased expression of matrix metalloproteinases and degradation of the basement membrane...
February 12, 2019: Cancer Research
Anna Visa, Marta C Sallán, Oscar Maiques, Lía Alza, Elisabet Talavera, Ricard López-Ortega, Maria Santacana, Judit Herreros, Carles Cantí
T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacological blockers have limited selectivity for TTCC, and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cav3...
February 12, 2019: Cancer Research
Thomas P Howard, Taylor E Arnoff, Melinda R Song, Andrew O Giacomelli, Xiaofeng Wang, Andrew L Hong, Neekesh V Dharia, Su Wang, Francisca Vazquez, Minh-Tam Pham, Ann M Morgan, Franziska Wachter, Gregory H Bird, Guillaume Kugener, Elaine M Oberlick, Matthew G Rees, Hong L Tiv, Justin H Hwang, Katherine H Walsh, April Cook, John M Krill-Burger, Aviad Tsherniak, Prafulla C Gokhale, Peter J Park, Kimberly Stegmaier, Loren D Walensky, William C Hahn, Charles W M Roberts
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4...
February 12, 2019: Cancer Research
Wei Wang, Nicole M Chapman, Bo Zhang, Mingqi Li, Meiyun Fan, R Nicholas Laribee, M Raza Zaidi, Lawrence M Pfeffer, Hongbo Chi, Zhao-Hui Wu
Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of skin lesions and establishment of tumors by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here we report that UVR exposure significantly increased expression of immune checkpoint molecule PD-L1 in melanoma cells. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the receptor for advanced glycation endproducts (RAGE) receptor to promote NF-kB- and IRF3-dependent transcription of PD-L1 in melanocytes...
February 8, 2019: Cancer Research
Bok Sil Hong, Han Suk Ryu, Namshin Kim, Jisun Kim, Eunshin Lee, Hyunhye Moon, Kyoung Hyoun Kim, Min-Sun Jin, Nam Hoon Kwon, Sunghoon Kim, Donghyun Kim, Doo Hyun Chung, Kyeonghun Jeong, Kwangsoo Kim, Ki Yoon Kim, Han-Byoel Lee, Wonshik Han, Jihui Yun, Jong-Il Kim, Dong-Young Noh, Hyeong-Gon Moon
Various microRNAs (miRNAs) play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared to normal breast tissues, and its expression levels were associated with increased survival outcome in breast cancer patients. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells...
February 8, 2019: Cancer Research
Shuo Huang, Zhongyu Wang, Jie Zhou, Jiani Huang, Li Zhou, Jing Luo, Yisong Y Wan, Haixia Long, Bo Zhu
Enhancer of Zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on anti-tumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFN-γ+CD8+ T cells, which are involved in anti-tumor immunity...
February 8, 2019: Cancer Research
Koji Fukuda, Shinji Takeuchi, Sachiko Arai, Ryohei Katayama, Shigeki Nanjo, Azusa Tanimoto, Akihiro Nishiyama, Takayuki Nakagawa, Hirokazu Taniguchi, Takeshi Suzuki, Tadaaki Yamada, Hiroshi Nishihara, Hironori Ninomiya, Yuichi Ishikawa, Satoko Baba, Kengo Takeuchi, Atsushi Horiike, Noriko Yanagitani, Makoto Nishio, Seiji Yano
Mutations in the ALK gene are detectable in ~40% of ALK-rearranged lung cancers resistant to ALK inhibitors. While epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK-inhibitor resistance is largely unknown. In this study, we report that both ALK mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in an ALK-rearranged lung cancer patient. Digital PCR analyses combined with microdissection after immunohistochemical staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers...
February 8, 2019: Cancer Research
Aparna Shinde, Shana D Hardy, Dongwook Kim, Saeed S Akhand, Mohit Kumar Jolly, Wen-Hung Wang, Joshua C Anderson, Ryan B Khodadadi, Wells S Brown, Jason T George, Sheng Liu, Jun Wan, Herbert Levine, Christopher D Willey, Casey J Krusemark, Robert L Geahlen, Michael K Wendt
The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGF-β to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib...
February 7, 2019: Cancer Research
Lianpin Wu, Baozhu Yi, Shi Wei, Dapeng Yao, Youhua He, Gurudatta Naik, Sejong Bae, Xiaoguang M Liu, Wei-Hsiung Yang, Guru Sonpavde, Runhua Liu, Lizhong Wang
Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here we characterize the functional crosstalk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62...
February 7, 2019: Cancer Research
Feifei Wang, Songli Zhu, Laura A Fisher, Ling Wang, Nicholas J Eurek, James K Wahl, Li Lan, Aimin Peng
Poly (ADP-ribose) polymerases (PARP), particularly PARP1, play an essential role in the detection and repair of DNA single strand breaks (SSB) and double strand breaks (DSB). PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that PNUTS is a robust binding partner of PARP1...
February 7, 2019: Cancer Research
Yumi Yokoyama, Erin D Lew, Ruth Seelige, Elizabeth A Tindall, Colin Walsh, Patrick C Fagan, Jack Y Lee, Robin Nevarez, Joanne Oh, Kathleen D Tucker, Marissa Chen, Amy Diliberto, Heather Vaaler, Kristen M Smith, Amanda Albert, Gary Li, Jack D Bui
Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant anti-tumor activity in multiple syngeneic tumor models...
February 5, 2019: Cancer Research
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