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Molecular Cancer Research: MCR

Daniella Bianchi-Frias, Mamatha Damodarasamy, Susana A Hernandez, Rui M Gil da Costa, Funda Vakar-Lopez, Ilsa Coleman, May J Reed, Peter S Nelson
The incidence of prostate cancer (PC) is directly linked to age, but age-associated changes that facilitate PC development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on PC behavior. PC cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared to young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis or angiogenesis...
September 17, 2018: Molecular Cancer Research: MCR
Li Jia, Shahrzad Rafiei, Bin Gui, Jiaxin Wu, X Shirley Liu, Adam S Kibel
While androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer (mPCa), incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for PCa growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein-coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT...
September 17, 2018: Molecular Cancer Research: MCR
Sonia Manca, Cole P Frisbie, Chad A LaGrange, Carol A Casey, Jean-Jack M Riethoven, Armen Petrosyan
Multiple epidemiological observations and meta-analysis clearly indicate the link between alcohol abuse and the incidence and progression of prostate cancer (PCa); however, the mechanism remains enigmatic. Recently it was found that ethanol (EtOH) induces disorganization of the Golgi complex caused by impaired function of the largest Golgi matrix protein, giantin (GOLGB1), which, in turn, alters the Golgi docking of resident Golgi proteins. Here, it is determined that in normal prostate cells, histone deacetylase 6 (HDAC6), the known regulator of androgen receptor (AR)-signaling, localizes in the cytoplasm and nucleus, while its kinase, glycogen synthase kinase β (GSK3β), primarily resides in the Golgi...
September 17, 2018: Molecular Cancer Research: MCR
D Vicky de Boer, Arjen Brink, Marijke Buijze, Marijke Stigter-van Walsum, Keith D Hunter, Bauke Ylstra, Elisabeth Bloemena, C René Leemans, Ruud H Brakenhoff
Head and neck squamous cell carcinomas (HNSCCs) develop in fields of genetically altered cells. These fields are often dysplastic and a subset can be recognized as (erythro)leukoplakia, but most are macroscopically invisible. There is a lack of adequate treatment options to eradicate these fields, while they underlie the development of primary tumors as well as part of the local relapses. Unfortunately, there are almost no representative cellular models available to identify suitable treatment options. To this end, clinical biopsy specimens (n=98) were cultured from normal appearing mucosa of the surgical margins of patients with primary HNSCCs (n=32) to generate precancer cell culture models...
September 17, 2018: Molecular Cancer Research: MCR
Yun Wei, Victor Maximov, A Sorana Morrissy, Michael D Taylor, David C Pallas, Anna Marie Kenney
Medulloblastomas, the most common malignant pediatric brain tumors, have been genetically defined into four subclasses, namely WNT-activated, sonic hedgehog (SHH)-activated, Group 3 and Group 4. Approximately 30% of medulloblastomas have aberrant SHH signaling and thus are referred to as SHH-activated medulloblastoma. The tumor suppressor gene TP53 has been recently recognized as a prognostic marker for SHH-activated medulloblastoma patients; patients with mutant TP53 have a significantly worse outcome than those with wild-type TP53...
September 17, 2018: Molecular Cancer Research: MCR
Christina Schug, Aayush Gupta, Sarah Urnauer, Katja Steiger, Phyllis Fung-Yi Cheung, Christian Neander, Konstantinos Savvatakis, Kathrin A Schmohl, Marija Trajkovic-Arsic, Nathalie Schwenk, Markus Schwaiger, Peter J Nelson, Jens T Siveke, Christine Spitzweg
The sodium iodide symporter (SLC5A5/NIS) as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSCs), based on their tumor-homing abilities, show great promise as tumor-selective NIS gene delivery vehicles for non-thyroidal tumors. Towards this clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC)...
September 17, 2018: Molecular Cancer Research: MCR
Julie A Barta, Steven B McMahon
Lung cancer, the leading cause of cancer-related mortality in the US, occurs primarily due to prolonged exposure to an array of carcinogenic compounds in cigarette smoke. These carcinogens create bulky DNA adducts, inducing alterations including missense mutations in the tumor suppressor gene TP53. TP53 is the most commonly mutated gene in many human cancers, and a specific set of these variants are enriched in lung cancer (at amino acid residues V157, R158, and A159). This perspective postulates that lung-enriched mutations can be explained, in part, by biological selection for oncogenic gain-of-function (GOF) mutant p53 alleles at V157, R158, and A159...
September 17, 2018: Molecular Cancer Research: MCR
Thomas J Rogers, Jessica L Christenson, Lisa I Greene, Kathleen I O'Neill, Michelle M Williams, Michael A Gordon, Travis Nemkov, Angelo D'Alessandro, Greg D DeGala, Jimin Shin, Aik-Choon Tan, Diana M Cittelly, James R Lambert, Jennifer K Richer
Tryptophan-2,3-dioxygenase (TDO2), a rate-limiting enzyme in the tryptophan catabolism pathway, is induced in triple-negative breast cancer (TNBC) by inflammatory signals and anchorage-independent conditions. TNBC express extremely low levels of the microRNA-200 (miR-200) family compared to estrogen receptor-positive (ER+) breast cancer. In normal epithelial cells and ER+ breast cancers and cell lines, high levels of the family member, miR-200c serve to target and repress genes involved in epithelial-to-mesenchymal transition (EMT)...
September 13, 2018: Molecular Cancer Research: MCR
Yue Xue, Lihua Lai, Wenwen Lian, Xintao Tu, Jiaojiao Zhou, Ping Dong, Dan Su, Xiaojia Wang, Xuetao Cao, Yiding Chen, Qingqing Wang
The presence of cancer stem cells (CSCs) which possess the ability of self-renewal and cancer-initiation is correlated with poor prognosis and drug resistance of breast cancer patients. But the molecular regulatory networks for maintenance of CSC function still remain unclear. Here we identified an estrogen inducible gene FXYD3, whose expression is significantly up-regulated in ER+ breast CSCs, is a critical player for regulating ER+ breast CSCs function. FXYD3 amplification is crucial in mediating tamoxifen-resistance in ER+ breast cancer cells...
September 11, 2018: Molecular Cancer Research: MCR
Abid R Mattoo, Alex Joun, J Milburn Jessup
MCL-1, a member of the anti-apoptotic BCL2 family, is a pro-survival protein with an essential DNA repair function. This study aims to test whether inhibition of protein synthesis by mTOR complex (mTORC) inhibitors depletes MCL-1, suppresses Homologous Recombination (HR) repair and sensitizes cancer cells to PARP inhibitors. Treatment with Everolimus decreases MCL-1 in colorectal carcinomas (CRC) and small cell lung cancer (SCLC) cells but not glioblastoma multiforme (GBM) cells with a PTEN mutational background...
September 10, 2018: Molecular Cancer Research: MCR
Grace P Leung, Tianshu Feng, Frederic D Sigoillot, Felipe Correa Geyer, Matthew D Shirley, David A Ruddy, Daniel Rakiec, Alyson K Freeman, Jeffrey A Engelman, Mariela Jaskelioff, Darrin D Stuart
The most frequent genetic alterations in melanoma are gain-of-function (GOF) mutations in BRAF, which result in RAF-MEK-ERK signaling pathway addiction. Despite therapeutic success of RAF and MEK inhibitors in treating BRAFV600 mutant tumors, a major challenge is the inevitable emergence of drug resistance, which often involves reactivation of the MAPK pathway. Interestingly, resistant tumors are often sensitive to drug withdrawal, suggesting that hyperactivation of the MAPK pathway is not tolerated. To further characterize this phenomenon, isogenic models of inducible MAPK hyperactivation in BRAFV600E melanoma cells were generated by overexpression of ERK2...
September 10, 2018: Molecular Cancer Research: MCR
Feifei Wang, Ling Wang, Laura A Fisher, Chunling Li, Weidong Wang, Aimin Peng
Mitotic progression is regulated largely by reversible phosphorylation events that are mediated by mitotic kinases and phosphatases. Protein phosphatase 1 (PP1) has been shown to play a crucial role in regulation of mitotic entry, progression, and exit. We previously observed, in Xenopus egg extracts, that phosphatase 1 nuclear targeting subunit (PPP1R10/PNUTS) acts as a mitotic regulator by negatively modulating PP1. This study investigates the role of PNUTS in mitotic progression in mammalian cells, and demonstrates that PNUTS expression is elevated in mitosis and depletion partially blocks mitotic entry...
September 6, 2018: Molecular Cancer Research: MCR
Isabel Romero-Calvo, Christopher Weber, Mohana Ray, Miguel Brown, Kori Kirby, Rajib K Nandi, Tiha M Long, Samantha M Sparrow, Andrey Ugolkov, Wenan Qiang, Yilin Zhang, Tonya Brunetti, Hedy Kindler, Jeremy P Segal, Andrey Rzhetsky, Andrew P Mazar, Mary M Buschmann, Ralph Weichselbaum, Kevin Roggin, Kevin P White
Patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid systems show great promise for understanding the biological underpinnings of disease and advancing therapeutic precision medicine. Despite the increased use of organoids, the fidelity of molecular features, genetic heterogeneity, and drug response to the tumor of origin remain important unanswered questions limiting their utility. To address this gap in knowledge, primary tumor- and PDX-derived organoids, and 2D cultures for in-depth genomic and histopathological comparisons to the primary tumor were created...
August 31, 2018: Molecular Cancer Research: MCR
Yanding Zhao, Evelien Schaafsma, Ivan P Gorlov, Eva Hernando, Nancy E Thomas, Ronglai Shen, Mary Jo Turk, Marianne Berwick, Christopher I Amos, Chao Cheng
Melanoma is the most aggressive type of skin cancer in the United States with an increasing incidence. Melanoma lesions often exhibit high immunogenicity, with infiltrating immune cells playing important roles in regression of tumors occurring spontaneously or caused by therapeutic treatment. Computational and experimental methods have been used to estimate the abundance of immune cells in tumors, but their applications are limited by the requirement of large gene sets or multiple antibodies. While the prognostic role of immune cells has been appreciated, a systematic investigation of their association with clinical factors, genomic features, prognosis and treatment response in melanoma is still lacking...
August 31, 2018: Molecular Cancer Research: MCR
Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Funazo, Koh Furugaki, Yasushi Yoshimura, Hitomi Ajimizu, Ryoko Okutani, Yuto Yasuda, Takashi Nomizo, Kiyoshi Uemasu, Koichi Hasegawa, Hironori Yoshida, Yoshitaka Yagi, Hiroki Nagai, Yuichi Sakamori, Mitsuyoshi Ueda, Toyohiro Hirai, Young Hak Kim
The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed...
August 31, 2018: Molecular Cancer Research: MCR
Akshata R Udyavar, Ching-Wei Chang, Jill M Spoerke, Junko Aimi, Heidi M Savage, Anneleen Daemen, Joyce O'Shaughnessey, Richard Bourgon, Mark R Lackner, Timothy R Wilson
The identification of early breast cancer (eBC) patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathological features such as tumor size and nodal status, as well as several gene expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities...
August 31, 2018: Molecular Cancer Research: MCR
Maria Alexiadis, Simone M Rowley, Simon Chu, Dilys T H Leung, Colin J R Stewart, Kaushalya Christmalee Amarasinghe, Ian G Campbell, Peter J Fuller
Adult granulosa cell tumor (aGCT), the most common malignant ovarian sex cord-stromal tumor, is characterized by the forkhead transcription factor FOXL2 p.C134W somatic mutation. Late recurrences are relatively common but the molecular mechanisms of relapse or aggressive behavior are not known. The mutational landscape of FOXL2 p.C134W mutation positive tumors (n=22) was determined using whole exome sequencing (WES). An average of 64 coding and essential splice-site variants was identified per tumor. As the TERT promoter region is poorly covered by the WES, targeted sequencing identified the TERT -124C>T promoter mutation as the only recurrent mutation (~40% of cases)...
August 30, 2018: Molecular Cancer Research: MCR
Naser Jafari, James Drury, Andrew J Morris, Fredrick O Onono, Payton D Stevens, Tianyan Gao, Jinpeng Liu, Chi Wang, Eun Y Lee, Heidi L Weiss, B Mark Evers, Yekaterina Y Zaytseva
Metastasis is the most common cause of death in colorectal cancer (CRC) patients. Fatty acid synthase (FASN) and sphingosine kinase-1 and -2 (SPHK1 and 2) are overexpressed in many cancers, including CRC. However, the contribution of FASN-mediated upregulation of sphingolipid metabolism to CRC metastasis and the potential of these pathways as targets for therapeutic intervention remain unknown. This study, determined that SPHKs are overexpressed in CRC as compared to normal mucosa. FASN expression significantly correlated with SPHK2 expression in data sets from The Cancer Genome Atlas (TCGA) and a CRC tumor microarray...
August 28, 2018: Molecular Cancer Research: MCR
Lisa I Greene, Tullia C Bruno, Jessica L Christenson, Angelo D'Alessandro, Rachel Culp-Hill, Kathleen Torkko, Virginia F Borges, Jill E Slansky, Jennifer K Richer
Tryptophan catabolism is an attractive target for reducing tumor progression and improving antitumor immunity in multiple cancers. Tumor infiltration by CD8 T cells correlates with improved prognosis in triple-negative breast cancer (TNBC) and a significant effort is underway to improve CD8 T cell antitumor activity. In this study, primary human immune cells were isolated from the peripheral blood of patients and used to demonstrate that the tryptophan catabolite kynurenine induces CD8 T cell death. Furthermore, it is demonstrated that anchorage-independent TNBC utilizes the tryptophan catabolizing enzyme tryptophan 2,3-dioxygenase (TDO) to inhibit CD8 T cell viability...
August 24, 2018: Molecular Cancer Research: MCR
Hitoshi Shiota, Janine E Elya, Artyom A Alekseyenko, Pauline M Chou, Shelby A Gorman, Olena Barbash, Kelly Becht, Kristina Danga, Mitzi I Kuroda, Valentina Nardi, Christopher A French
NUT Carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of NUT-fusion oncogenes resulting from chromosomal translocation. In most cases, the NUT gene (NUTM1) is fused to bromodomain containing 4 (BRD4) forming the BRD4-NUT oncogene. Here, a novel fusion partner to NUT was discovered using next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT-fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex...
August 23, 2018: Molecular Cancer Research: MCR
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