Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors
Many tumors display intracellular heterogeneity with subsets of cancer stem cells (CSC) that sustain tumor growth, recurrence, and therapy resistance. Cancer-associated fibroblasts (CAF) have been shown to support and regulate CSC function. Here, we investigate the interactions between CSCs and CAFs in mammary gland tumors driven by combined activation of Wnt/β-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secrete the Hedgehog ligand SHH, which regulate CAFs via paracrine activation of Hedgehog signaling. CAFs subsequently secrete factors that promote expansion and self-renewal of ...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Giovanni Valenti, Hazel M. Quinn, Guus J.J.E. Heynen, Linxiang Lan, Jane D. Holland, Regina Vogel, Annika Wulf-Goldenberg, Walter Birchmeier Tags: Tumor and Stem Cell Biology Source Type: research
Distinct Levels of Radioresistance in Lgr5+ Colonic Epithelial Stem Cells versus Lgr5+ Small Intestinal Stem Cells
Although small and large intestines possess seemingly similar Wnt-driven leucine-rich repeat-containing G protein–coupled receptor 5 (Lgr5)+ adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. Employing Lgr5-lacZ transgenic mice and Lgr5 in situ hybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistant in vivo than small intestinal crypt base columnar stem cells (CBC; D0 = 6.0 ± 0.3 Gy vs. 1.3 ± 0.1, respectively; P (Source: Cancer Research)
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Guoqiang Hua, Chu Wang, Yan Pan, Zhaoshi Zeng, Sang Gyu Lee, Maria Laura Martin, Adriana Haimovitz-Friedman, Zvi Fuks, Philip B. Paty, Richard Kolesnick Tags: Tumor and Stem Cell Biology Source Type: research
Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models
Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize a positron emission tomography (PET) probe for imaging DIPG in vivo. In human histological tissues, the probes target, PARP1, was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model, and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1-expressing cells. Comparison with other imagin...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Susanne Kossatz, Brandon Carney, Melanie Schweitzer, Giuseppe Carlucci, Vesselin Z. Miloushev, Uday B. Maachani, Prajwal Rajappa, Kayvan R. Keshari, David Pisapia, Wolfgang A. Weber, Mark M. Souweidane, Thomas Reiner Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues
Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies conf...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Christina D. Drenberg, Alice A. Gibson, Stanley B. Pounds, Lei Shi, Dena P. Rhinehart, Lie Li, Shuiying Hu, Guoqing Du, Anne T. Nies, Matthias Schwab, Navjotsingh Pabla, William Blum, Tanja A. Gruber, Sharyn D. Baker, Alex Sparreboom Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
E3 Ubiquitin Ligase UBR5 Drives the Growth and Metastasis of Triple-Negative Breast Cancer
Patients with triple-negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. Here, we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole-exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinom...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Liqiu Liao, Mei Song, Xin Li, Lili Tang, Tuo Zhang, Lixing Zhang, Yihang Pan, Lotfi Chouchane, Xiaojing Ma Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors
In this study, we report that the Src–AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. Cancer Res; 77(8); 2078–89. ©2017 AACR. (Source: Cancer Research)
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Shigenari Nukaga, Hiroyuki Yasuda, Katsuya Tsuchihara, Junko Hamamoto, Keita Masuzawa, Ichiro Kawada, Katsuhiko Naoki, Shingo Matsumoto, Sachiyo Mimaki, Shinnosuke Ikemura, Koichi Goto, Tomoko Betsuyaku, Kenzo Soejima Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells
Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5–GPX4 pathway mediated ferroptosis resistance, limiting the anticancer a...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Shan Zhu, Qiuhong Zhang, Xiaofan Sun, Herbert J. Zeh III, Michael T. Lotze, Rui Kang, Daolin Tang Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Oncolytic Adenoviral Delivery of an EGFR-Targeting T-cell Engager Improves Antitumor Efficacy
In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell–engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic properties in vitro. cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE–infected cells, and the secreted BiTEs bound specifically to both CD3+ and EGFR+ cells. ...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Carlos Alberto Fajardo, Sonia Guedan, Luis Alfonso Rojas, Rafael Moreno, Marcel Arias-Badia, Jana de Sostoa, Carl H. June, Ramon Alemany Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors
In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no antitumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T cells enhanced antitumor activity comp...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Kiyonori Tanoue, Amanda Rosewell Shaw, Norihiro Watanabe, Caroline Porter, Bhakti Rana, Stephen Gottschalk, Malcolm Brenner, Masataka Suzuki Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Ex Vivo Explant Cultures of Non-Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy
To improve treatment outcomes in non–small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo. Notabl...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Ellie Karekla, Wen-Jing Liao, Barry Sharp, John Pugh, Helen Reid, John Le Quesne, David Moore, Catrin Pritchard, Marion MacFarlane, James Howard Pringle Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
Radiation Resistance in KRAS-Mutated Lung Cancer Is Enabled by Stem-like Properties Mediated by an Osteopontin-EGFR Pathway
Lung cancers with activating KRAS mutations are characterized by treatment resistance and poor prognosis. In particular, the basis for their resistance to radiation therapy is poorly understood. Here, we describe a radiation resistance phenotype conferred by a stem-like subpopulation characterized by mitosis-like condensed chromatin (MLCC), high CD133 expression, invasive potential, and tumor-initiating properties. Mechanistic investigations defined a pathway involving osteopontin and the EGFR in promoting this phenotype. Osteopontin/EGFR–dependent MLCC protected cells against radiation-induced DNA double-strand breaks a...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Meng Wang, Jing Han, Lynnette Marcar, Josh Black, Qi Liu, Xiangyong Li, Kshithija Nagulapalli, Lecia V. Sequist, Raymond H. Mak, Cyril H. Benes, Theodore S. Hong, Kristin Gurtner, Mechthild Krause, Michael Baumann, Jing X. Kang, Johnathan R. Whetstine, He Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by Targeting ADAM9 and TGFBR2
In this study, we screened a library of 1120 miRNA for their ability to transcriptionally activate the E-cadherin gene CDH1 in a promoter reporter assay as a measure of EMT reversal. By this approach, we defined miR-520f as a novel EMT-reversing miRNA. miR-520f expression was sufficient to restore endogenous levels of E-cadherin in cancer cell lines exhibiting strong or intermediate mesenchymal phenotypes. In parallel, miR-520f inhibited invasive behavior in multiple cancer cell systems and reduced metastasis in an experimental mouse model of lung metastasis. Mechanistically, miR-520f inhibited tumor cell invasion by direc...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Jasmijn G.M. van Kampen, Onno van Hooij, Cornelius F. Jansen, Frank P. Smit, Paula I. van Noort, Iman Schultz, Roel Q.J. Schaapveld, Jack A. Schalken, Gerald W. Verhaegh Tags: Molecular and Cellular Pathobiology Source Type: research
eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth
In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Bi...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Jan Strnadel, Sunkyu Choi, Ken Fujimura, Huawei Wang, Wei Zhang, Meghan Wyse, Tracy Wright, Emilie Gross, Carlos Peinado, Hyun Woo Park, Jack Bui, Jonathan Kelber, Michael Bouvet, Kun-Liang Guan, Richard L. Klemke Tags: Molecular and Cellular Pathobiology Source Type: research
Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer
The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound t...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Yuli Wang, Pengju Zhang, Yunshan Wang, Panpan Zhan, Chunyan Liu, Jian-Hua Mao, Guangwei Wei Tags: Molecular and Cellular Pathobiology Source Type: research
Sodium Channel Subunit SCNN1B Suppresses Gastric Cancer Growth and Metastasis via GRP78 Degradation
There remains a paucity of functional biomarkers in gastric cancer. Here, we report the identification of the sodium channel subunit SCNN1B as a candidate biomarker in gastric cancer. SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in gastric cancer cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in gastric cancer patients, especially those with late-stage disease. Functional studies demonstrated that SCNN1B overexpression was sufficient to suppress multiple features of cancer cell pat...
Source: Cancer Research - April 13, 2017 Category: Cancer & Oncology Authors: Yun Qian, Chi Chun Wong, Jiaying Xu, Huarong Chen, Yanquan Zhang, Wei Kang, Hua Wang, Li Zhang, Weilin Li, Eagle S.H. Chu, Minnie Y.Y. Go, Philip W.Y. Chiu, Enders K.W. Ng, Francis K.L. Chan, Joseph J.Y. Sung, Jianmin Si, Jun Yu Tags: Molecular and Cellular Pathobiology Source Type: research
