KDM4 Inhibition Targets Breast Cancer Stem-like Cells
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Eric Metzger, Stella S. Stepputtis, Juliane Strietz, Bogdan–Tiberius Preca, Sylvia Urban, Dominica Willmann, Anita Allen, Fides Zenk, Nicola Iovino, Peter Bronsert, Amelie Proske, Marie Follo, Melanie Boerries, Elmar Stickeler, Jiangchun Xu, Michael Tags: Tumor and Stem Cell Biology Source Type: research
FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NF{kappa}B-BMP Signaling Cross-talk
Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, and molecular markers to improve early detection and predict outcomes are greatly needed. Here, we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs, where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q, where it is located, occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal, a...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Marco Chi-Chung Lau, Kai Yu Ng, Tin Lok Wong, Man Tong, Terence K. Lee, Xiao-Yan Ming, Simon Law, Nikki P. Lee, Annie L. Cheung, Yan-Ru Qin, Kwok Wah Chan, Wen Ning, Xin-Yuan Guan, Stephanie Ma Tags: Tumor and Stem Cell Biology Source Type: research
ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma
In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh ...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Abibatou Ndoye, Anna Budina-Kolomets, Curtis H. Kugel III, Marie R. Webster, Amanpreet Kaur, Reeti Behera, Vito W. Rebecca, Ling Li, Patricia A. Brafford, Qin Liu, Y.N. Vashisht Gopal, Michael A. Davies, Gordon B. Mills, Xiaowei Xu, Hong Wu, Meenhard Herl Tags: Tumor and Stem Cell Biology Source Type: research
Novel SEC61G-EGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens
This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI). One highly tumorigenic MI line harbored membrane-bound, constitutively active, truncated EGFR. Two EGFR mutants (ΔN566 and ΔN599) were identified as products of intrachromosomal rearrangements fusing the 3′ co...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tiziana Servidei, Daniela Meco, Valentina Muto, Alessandro Bruselles, Andrea Ciolfi, Nadia Trivieri, Matteo Lucchini, Roberta Morosetti, Massimiliano Mirabella, Maurizio Martini, Massimo Caldarelli, Anna Lasorella, Marco Tartaglia, Riccardo Riccardi Tags: Tumor and Stem Cell Biology Source Type: research
Lysyl Oxidase-like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer
The lysyl oxidase–like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 ...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Fernando Salvador, Alberto Martin, Celia Lopez–Menendez, Gema Moreno–Bueno, Vanesa Santos, Alberto Vazquez–Naharro, Patricia G. Santamaria, Saleta Morales, Pierre R. Dubus, Laura Muinelo–Romay, Rafael Lopez–Lopez, Jason C. Tu Tags: Tumor and Stem Cell Biology Source Type: research
ANGPTL1 Interacts with Integrin {alpha}1{beta}1 to Suppress HCC Angiogenesis and Metastasis by Inhibiting JAK2/STAT3 Signaling
Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here, we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2–mediated antiapoptotic pathway and decreased cell migration and invasi...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Qian Yan, Lingxi Jiang, Ming Liu, Dandan Yu, Yu Zhang, Yan Li, Shuo Fang, , Ying-Hui Zhu, Yun-Fei Yuan, Xin-Yuan Guan Tags: Tumor and Stem Cell Biology Source Type: research
KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling
The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation ...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: James V. Neiswender, Robert L. Kortum, Caitlin Bourque, Melissa Kasheta, Leonard I. Zon, Deborah K. Morrison, Craig J. Ceol Tags: Tumor and Stem Cell Biology Source Type: research
Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587
Tumor–stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA-hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem-like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exosomal content identified miR-1587 as a mediator of the exosomal effects on GSCs, in part via downregulation of the tumor-suppress...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Javier Figueroa, Lynette M. Phillips, Tal Shahar, Anwar Hossain, Joy Gumin, Hoon Kim, Andrew J. Bean, George A. Calin, Juan Fueyo, Edgar T. Walters, Raghu Kalluri, Roel G. Verhaak, Frederick F. Lang Tags: Tumor and Stem Cell Biology Source Type: research
Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation
Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC â...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Laura E. Jackson, Sucheta Kulkarni, Huabo Wang, Jie Lu, James M. Dolezal, Sivakama S. Bharathi, Sarangarajan Ranganathan, Mulchand S. Patel, Rahul Deshpande, Frances Alencastro, Stacy G. Wendell, Eric S. Goetzman, Andrew W. Duncan, Edward V. Prochownik Tags: Molecular and Cellular Pathobiology Source Type: research
MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway
Long noncoding RNAs (lncRNA) participate in carcinogenesis and tumor progression in lung cancer. Here, we report the identification of a lncRNA signature associated with metastasis of non–small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Tao Yu, Yingjun Zhao, Zhixiang Hu, Jing Li, Dandan Chu, Jiwei Zhang, Zhe Li, Bing Chen, Xiao Zhang, Hongyu Pan, Shengli Li, Hechun Lin, Lei Liu, Mingxia Yan, Xianghuo He, Ming Yao Tags: Molecular and Cellular Pathobiology Source Type: research
YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation
Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non–small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo. Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficient...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Hsinyi Huang, Wenjing Zhang, Yafang Pan, Yijun Gao, Lei Deng, Fuming Li, Fei Li, Xueyan Ma, Shenda Hou, Jing Xu, Peixue Li, Xiaoxun Li, Guohong Hu, Cheng Li, Haiquan Chen, Lei Zhang, Hongbin Ji Tags: Molecular and Cellular Pathobiology Source Type: research
PADI2-Mediated Citrullination Promotes Prostate Cancer Progression
Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo. Cytoplasmic PADI2 protected the androgen receptor (AR) again...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Lin Wang, Guanhua Song, Xiang Zhang, Tingting Feng, Jihong Pan, Weiwen Chen, Muyi Yang, Xinnuo Bai, Yu Pang, Jindan Yu, Jinxiang Han, Bo Han Tags: Molecular and Cellular Pathobiology Source Type: research
Upregulation of Cystathionine-{beta}-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis
The trans-sulfuration enzyme cystathionine-β-synthase (CBS) and its product hydrogen sulfide (H2S) are aberrantly upregulated in colorectal cancers, where they contribute to tumor growth and progression by both autocrine and paracrine mechanisms. However, it is unknown whether the CBS/H2S axis plays a role in colorectal carcinogenesis. Here, we report upregulation of CBS in human biopsies of precancerous adenomatous polyps and show that forced upregulation of CBS in an adenoma-like colonic epithelial cell line is sufficient to induce metabolic and gene expression profiles characteristic of colorectal cancer cells. Differe...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Ches'Nique M. Phillips, John R. Zatarain, Michael E. Nicholls, Craig Porter, Steve G. Widen, Ketan Thanki, Paul Johnson, Muhammad U. Jawad, Mary P. Moyer, James W. Randall, Judith L. Hellmich, Manȷit Maskey, Suimin Qiu, Thomas G. Wood, Nadiya Druzh Tags: Molecular and Cellular Pathobiology Source Type: research
miR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells
In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b–target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK–SRC–CRKL...
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Ying Z. Mazzu, Yulan Hu, Rajesh K. Soni, Kelly M. Mojica, Li-Xuan Qin, Phaedra Agius, Zachary M. Waxman, Aleksandra Mihailovic, Nicholas D. Socci, Ronald C. Hendrickson, Thomas Tuschl, Samuel Singer Tags: Molecular and Cellular Pathobiology Source Type: research
Discovery of Human-Similar Gene Fusions in Canine Cancers
This study demonstrates similar gene fusion partners and mechanisms in human–dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine. Cancer Res; 77(21); 5721–7. ©2017 AACR. (Source: Cancer Research)
Source: Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: Ronan Ulve, Melanie Rault, Mathieu Bahin, Laetitia Lagoutte, Jerome Abadie, Clotilde De Brito, Jean–Michel Coindre, Nadine Botherel, Audrey Rousseau, Valentin Wucher, Edouard Cadieu, Catherine Thieblemont, Christophe Hitte, Laurence Cornevin, Floria Tags: Priority Report Source Type: research
