Cancer Research

Sylvain Ferrandon, Jennifer DeVecchio, Leonardo Duraes, Hanumant Chouhan, Georgios Karagkounis, Jacqueline Davenport, Matthew Orloff, David Liska, Matthew F Kalady
Neoadjuvant radiation is standard of care for locally advanced rectal cancer. Response to radiation is highly variable and directly linked with survival. However, there currently are no validated biomarkers or molecular targets to predict or improve radiation response, which would help develop personalized treatment and ideally targeted therapies. Here, we identified a novel biomarker, coenzyme A synthase (COASY), whose mRNA expression was consistently elevated in radioresistant human rectal cancers. This observation was validated in independent patient cohorts and further confirmed in colorectal cancer cell lines...
November 8, 2019: Cancer Research
Ana Rita Lourenco, Yi Ban, Michael J Crowley, Sharrell B Lee, Divya Ramchandani, Wei Du, Olivier Elemento, Jason T George, Mohit Kumar Jolly, Herbert Levine, Jianting Sheng, Stephen T C Wong, Nasser K Altorki, Dingcheng Gao
Metastases are responsible for the majority of breast cancer-associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing model (Tri-PyMT), in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFP+ to GFP+ due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors...
November 8, 2019: Cancer Research
Ming Yu, William D Hazelton, Georg E Luebeck, William M Grady
The incidence of cancer, adjusted for secular trends, is directly related to age, and advanced chronological age is one of the most significant risk factors for cancer. Organismal aging is associated with changes at the molecular, cellular and tissue levels and is affected by both genetic and environmental factors. The specific mechanisms through which these age-associated molecular changes contribute to the increased risk of aging-related disease, such as cancer, are incompletely understood. DNA methylation, a prominent epigenetic mark, also changes over a lifetime as part of an 'epigenetic aging' process...
November 6, 2019: Cancer Research
Rafael Ikemori, Marta Gabasa, Paula Duch, Miguel Vizoso, Paloma Bragado, Marselina Arshakyan, Iuliana-Cristiana Luis, Albert Marín, Sebastián Morán, Manuel Castro, Gemma Fuster, Sabrina Gea-Sorli, Toni Jauset, Laura Soucek, Luis M Montuenga, Manel Esteller, Eduard Monso, Victor Ivo Peinado, Pere Gascon, Cristina Fillat, Frank Hilberg, Noemí Reguart, Jordi Alcaraz
The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAFs) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non-small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs in vitro and patient samples...
November 6, 2019: Cancer Research
Yiru Zhang, Trang T T Nguyen, Enyuan Shang, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Junfei Zhao, Chang Shu, Consuelo Torrini, Maria J Sanchez-Quintero, Giulio Kleiner, Elena Bianchetti, Mike-Andrew Westhoff, Catarina M Quinzii, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin
The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacological (crizotinib) inhibition of c-MET...
November 6, 2019: Cancer Research
Maxine Umeh-Garcia, Catalina Simion, Pui-Yan Ho, Neelu Batra, Anastasia L Berg, Kermit L Carraway, Aiming Yu, Colleen Sweeney
miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor microRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of microRNA mimics. Here, we take a novel approach to produce a miR-127 pro-drug (miR-127PD), which we demonstrate is processed to mature, functional microRNA-127-3p in TNBC tumor cells...
November 6, 2019: Cancer Research
Molly Gale, Yao Li, Jian Cao, Zongzhi Zachary Liu, Marissa A Holmbeck, Meiling Zhang, Sabine M Lang, Lizhen Wu, Mariana Do Carmo, Swati Gupta, Keisuke Aoshima, Michael P DiGiovanna, David F Stern, David L Rimm, Gerald S Shadel, Xiang Chen, Qin Yan
Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function...
November 5, 2019: Cancer Research
Maria Laura Martin, Mohammad Adileh, Kuo-Shun Hsu, Guoqiang Hua, Sang Gyu Lee, Christy Li, John D Fuller, Jimmy A Rotolo, Sahra Bodo, Stefan Klingler, Adriana Haimovitz-Friedman, Joseph O Deasy, Zvi Fuks, Philip B Paty, Richard N Kolesnick
Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses while at clinically relevant intermediate doses double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities...
November 5, 2019: Cancer Research
Udayan Bhattacharya, Lilach Gutter-Kapon, Tal Kan, Ilanit Boyango, Uri Barash, Shi-Ming Yang, JingJing Liu, Miriam Gross-Cohen, Ralph D Sanderson, Yuval Shaked, Neta Ilan, Israel Vlodavsky
The emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel (PCT) and cisplatin, evidenced by increased expression of pro-inflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor re-growth and spread...
November 5, 2019: Cancer Research
Yuan-Yuan Qu, Rui Zhao, Hai-Liang Zhang, Qian Zhou, Fu-Jiang Xu, Xuan Zhang, Wen-Hao Xu, Ning Shao, Shu-Xian Zhou, Bo Dai, Yao Zhu, Guo-Hai Shi, Yi-Jun Shen, Yi-Ping Zhu, Cheng-Tao Han, Kun Chang, Yan Lin, Wei-Dong Zang, Wei Xu, Ding-Wei Ye, Shi-Min Zhao, Jian-Yuan Zhao
The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remains insufficiently understood. In this study we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid oxidation (FAO) and activation of de novo fatty acid (FA) synthesis, positively associated with ccRCC progression and predicted poor patient survival...
November 5, 2019: Cancer Research
Sathya Muralidhar, Anastasia Filia, Jérémie Nsengimana, Joanna Poźniak, Sally J O'Shea, Joey M Diaz, Mark Harland, Juliette A Randerson-Moor, Jörg Reichrath, Jonathan P Laye, Louise van der Weyden, David J Adams, D T Bishop, Julia Newton-Bishop
1α,25-dihydroxyvitamin D3 signals via the Vitamin D Receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As melanoma patients commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signalling and replicated the findings in TCGA metastases. VDR expression was independently protective for melanoma death in both primary and metastatic disease...
November 5, 2019: Cancer Research
Anees M Dauki, James S Blachly, Esko A Kautto, Sameera Ezzat, Mohamed H Abdel-Rahman, Christopher C Coss
Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in advanced HCC patients by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC data sets (1090 samples)...
November 4, 2019: Cancer Research
Jiawei Zhou, Yutong Liu, Yubo Zhang, Quefeng Li, Yanguang Cao
Over 50% of colorectal cancer (CRC) patients develop resistance after a transient response to therapy. Understanding tumor resistance from an evolutionary perspective leads to better predictions of treatment outcomes. The objectives of this study were to develop a computational framework to analyze tumor longitudinal measurements and recapitulate the individual evolutionary dynamics in metastatic CRC (mCRC) patients. A stochastic modeling framework was developed to depict the whole spectrum of tumor evolution prior to diagnosis and during and after therapy...
November 1, 2019: Cancer Research
Dan Georgess, Veena Padmanaban, Orit Katarina Sirka, Kester Coutinho, Alex Choi, Gabriela Frid, Neil M Neumann, Takanari Inoue, Andrew J Ewald
Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate ECM-directed protrusions, release from the epithelium, and migrate through the extracellular matrix...
November 1, 2019: Cancer Research
Alice Fletcher, Martin L Read, Caitlin E M Thornton, Dean P Larner, Vikki L Poole, Katie Brookes, Hannah R Nieto, Mohammed Alshahrani, Rebecca J Thompson, Gareth G Lavery, Iñigo Landa, James A Fagin, Moray J Campbell, Kristien Boelaert, Andrew S Turnell, Vicki E Smith, Christopher J McCabe
The sodium iodide symporter (NIS) is required for iodide uptake which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined...
October 31, 2019: Cancer Research
Paul C Moore, Jenny Y Qi, Maike Thamsen, Rajarshi Ghosh, Justin Peng, Micah J Gliedt, Rosa Meza-Acevedo, Rachel E Warren, Annie Hiniker, Grace E Kim, Dustin J Maly, Bradley J Backes, Feroz R Papa, Scott A Oakes
Master regulators of the unfolded protein response (UPR) IRE1alpha and PERK promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation...
October 31, 2019: Cancer Research
Muller Fabbri
Natural Killer (NK) cells are cytotoxic lymphocytes targeting virus-infected cells and cancer cells. Specific pro- and anti-killing signals modulate the overall ability of NK cells to kill cancer cells, however, several immune-escape mechanisms can be enacted by cancer cells to avoid NK-mediated killing. Recently, increasing evidence has shown that extracellular vesicles (EVs) released by NK cells carry proteins and microRNAs (miRs) able to exert an anti-tumoral effect, even within a highly immune-suppressive tumor microenvironment...
October 31, 2019: Cancer Research
Grace E Coggins, Alvin Farrel, Komal S Rathi, Colin M Hayes, Laura Scolaro, Jo Lynne Rokita, John M Maris
Relapsed neuroblastomas are enriched with activating mutations of the RAS-MAPK signaling pathway. The MEK1/2 inhibitor trametinib delays tumor growth but does not sustain regression in neuroblastoma preclinical models. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP1 as an additional driver of relapsed neuroblastomas, as well as a mediator of trametinib resistance in other cancers. Here, we used a highly annotated set of high-risk neuroblastoma cellular models to modulate YAP1 expression and RAS pathway activation to test if increased YAP1 transcriptional activity is a mechanism of MEK1/2 inhibition resistance in RAS-driven neuroblastomas...
October 31, 2019: Cancer Research
Seungbeom Ko, Joo Yeon Park, Yu-Kyoung Oh
Microbial carboxyl and catechol siderophores have been shown to have natural iron-chelating abilities, suggesting that hyaluronic acid (HA) and the catechol compound, gallic acid (GA), may have iron-coordinating activities. Here, a photoresponsive self-gelling hydrogel that was both injectable and could be applied to the skin was developed based on the abilities of HA and GA to form coordination bonds with ferric ions (Fe3+). The conjugate of HA and GA (HA-GA) instantly formed hydrogels in the presence of ferric ions and showed near infrared (NIR)-responsive photothermal properties...
October 31, 2019: Cancer Research
Robert S Oakes, Grace G Bushnell, Sophia M Orbach, Pridvi Kandagatla, Yining Zhang, Aaron H Morris, Matthew S Hall, Petrina LaFaire, Joseph T Decker, Rachel M Hartfield, Michael D Brooks, Max S Wicha, Jacqueline S Jeruss, Lonnie D Shea
Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy...
October 29, 2019: Cancer Research
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