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    Tumor-Educated Platelets as a Noninvasive Biomarker Source for Cancer Detection and Progression Monitoring.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
    Liquid biopsies represent a potential revolution in cancer diagnostics as a noninvasive method for detecting and monitoring diseases, complementary to or even replacing current tissue biopsy approaches. Several blood-based biosources and biomolecules, such as cell-free DNA and RNA, proteins, circulating tumor cells, and extracellular vesicles, have been explored for molecular test development. We recently discovered the potential of tumor-educated blood platelets (TEP) as a noninvasive biomarker trove for RNA biomarker panels. Read More

    Computational characterization of suppressive immune microenvironments in glioblastoma.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Faculty of Medicine and Life Sciences, University of Tampere
    The immunosuppressive microenvironment in glioblastoma (GBM) prevents an efficient antitumoral immune response and enables tumor formation and growth. Although an understanding of the nature of immunosuppression is still largely lacking, it is important for successful cancer treatment through immune system modulation. To gain insight into immunosuppression in GBM, we performed a computational analysis to model relative immune cell content and type of immune response in each GBM tumor sample from The Cancer Genome Atlas RNA-seq dataset. Read More

    Inactivation of citron kinase inhibits medulloblastoma progression by inducing apoptosis and cell senescence.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Molecular Biotechnologies and Health Sciences, University of Turin
    Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB consists of surgery followed by irradiation of the whole neuraxis and high-dose multi-agent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting MB growth without disturbing brain development is needed. Read More

    DDX3 activates CBC-eIF3-mediated translation of uORF-containing oncogenic mRNAs to promote metastasis in HNSCC.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Institute of Biomedical Sciences, Academia Sinica
    Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes including ATF4-modulated genes in an aggressive OSCC cell line. Read More

    Transcription factor YY1 promotes cell proliferation by directly activating the pentose phosphate pathway.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    College of Bioengineering, Chongqing University.
    Tumor cells alter their metablosim to meet their demand for macromolecules, support a high rate of proliferation as well as cope with oxidative stress. The transcription factor yin yang 1 (YY1) is upregulated in various types of tumors and is crucial for tumor cell proliferation and metastasis. However, its role in tumor cell metabolic reprogramming is poorly understood. Read More

    Attenuated TRAF3 fosters alternative activation of NF-κB and reduced expression of anti-viral interferon, TP53, and RB to promote HPV-positive head and neck cancers.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH
    Human papilloma viruses (HPV) are linked to an epidemic increase in oropharyngeal head and neck squamous cell carcinomas (HNSCC), which display viral inactivation of tumor suppressors TP53 and RB1 and rapid regional spread. However, the role of genomic alterations in enabling modulation of pathways that promote the aggressive phenotype of these cancers is unclear. Recently, a subset of HPV+ HNSCC has been shown to harbor novel genetic defects or decreased expression of TNF-receptor-associated-factor-3 (TRAF3). Read More

    Epithelial-mesenchymal transition in human prostate cancer demonstrates enhanced immune evasion marked by IDO1 expression.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Department of Pathology, Erasmus University Medical Center.
    Cancer invasion and metastasis are driven by epithelial-to-mesenchymal transition (EMT), yet the exact mechanisms that account for EMT in clinical prostate cancer are not fully understood. Expression of N-cadherin is considered a hallmark of EMT in clinical prostate cancer. In this study, we determined the molecular mechanisms associated with N-cadherin expression in prostate cancer patients. Read More

    Recurrent RARB Translocations in Acute Promyelocytic Leukemia lacking RARA Translocation.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    National Center For Child Health and Development
    Translocations of retinoic acid receptor-α (RARA), typically PML-RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Read More

    Influence of smoking, body mass index and other factors on the preventive effect of nonsteroidal anti-inflammatory drugs on colorectal cancer risk.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center.
    Nonsteroidal anti-inflammatory drugs (NSAIDs) use has consistently been associated with lower risk of colorectal cancer (CRC); however, studies showed inconsistent results on which cohort of individuals may benefit most. We performed multivariable logistic regression analysis to systematically test for the interaction between regular use of NSAIDs and other lifestyle and dietary factors on CRC risk among 11,894 cases and 15,999 controls. Fixed-effects meta-analyses were used for stratified analyses across studies for each risk factor and to summarize the estimates from interactions. Read More

    Neoadjuvant-intensive androgen deprivation therapy selects for prostate tumor foci with diverse subclonal oncogenic alterations.
    Cancer Res 2018 Jun 19. Epub 2018 Jun 19.
    Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center
    Primary prostate cancer (PCa) can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant PCa (mCRPC) remains unclear. In this study, we microdissected residual PCa foci in radical prostatectomies from 18 men treated with neoadjuvant intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors with no increase in neuroendocrine differentiation. Read More

    The endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids.
    Cancer Res 2018 Jun 18. Epub 2018 Jun 18.
    Laboratory of Medical Chemistry, GIGA Molecular Biology of Diseases, University of Liege, GIGA
    MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. Read More

    Circulating tumor cells undergoing EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma.
    Cancer Res 2018 Jun 18. Epub 2018 Jun 18.
    Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University
    To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) patients, we used an advanced CanPatrol™ CTC-enrichment technique and in situ hybridization (ISH) to enrich and classify CTC from blood samples. 101 of 112 (90.18%) HCC patients were CTC-positive, even with early-stage disease. Read More

    Case Studies of Gastric, Lung, and Oral Cancer Connect Etiologic Agent Prevalence to Cancer Incidence.
    Cancer Res 2018 Jun;78(12):3386-3396
    Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
    Obtaining detailed individual-level data on both exposure and cancer outcomes is challenging, and it is difficult to understand and characterize how temporal aspects of exposures translate into cancer risk. We show that, in lieu of individual-level information, population-level data on cancer incidence and etiologic agent prevalence can be leveraged to investigate cancer mechanisms and to better characterize and predict cancer trends. We use mechanistic carcinogenesis models [multistage clonal expansion (MSCE) models] and data on smoking, (), and HPV infection prevalence to investigate trends of lung, gastric, and HPV-related oropharyngeal cancers. Read More

    EWS/ETS-driven Ewing Sarcoma requires BET bromodomain proteins.
    Cancer Res 2018 Jun 13. Epub 2018 Jun 13.
    Cancer Biology, University of Pennsylvania
    The EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has been unsuccessful; however, identifying mediators of the EWS/ETS function could offer new therapeutic options. Here we describe the dependency of EWS/ETS-driven transcription upon chromatin reader BET bromdomain proteins and investigate the potential of BET inhibitors in treating EWS. Read More

    Flightless-I blocks p62-mediated recognition of LC3 to impede selective autophagy and promote breast cancer progression.
    Cancer Res 2018 Jun 13. Epub 2018 Jun 13.
    School of Life Sciences, Xiamen University
    p62 is a receptor that facilitates selective autophagy by interacting simultaneously with cargoes and LC3 protein on the autophagosome to maintain cellular homeostasis. However, the regulatory mechanism(s) behind this process and its association with breast cancer remain to be elucidated. Here we report that Flightless-I (FliI), a novel p62-interacting protein, promotes breast cancer progression by impeding selective autophagy. Read More

    Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics And Tumor Cell Movements.
    Cancer Res 2018 Jun 13. Epub 2018 Jun 13.
    Tumor Microenvironment and Metastasis Program, The Wistar Institute
    Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. Read More

    Mcl-1 phosphorylation without degradation mediates sensitivity to HDAC inhibitors by liberating BH3-only proteins.
    Cancer Res 2018 Jun 12. Epub 2018 Jun 12.
    Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center
    Mcl-1, a pro-survival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anti-cancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. Read More

    Integrative genome-wide analysis of long noncoding RNAs in diverse immune cell types of melanoma patients.
    Cancer Res 2018 Jun 12. Epub 2018 Jun 12.
    Epidemiology and Public Health, University of Maryland School of Medicine
    Genome-wide identification and characterization of long non-coding RNAs (lncRNAs) in individual immune cell lineages helps us better understand the driving mechanisms behind melanoma and advance personalized patient treatment. To elucidate the transcriptional landscape in diverse immune cell types of peripheral blood cells (PBC) in stage IV melanoma, we used whole transcriptome RNA sequencing to profile lncRNAs in CD4+, CD8+, and CD14+ PBC from 132 patient samples. Our integrative computational approach identified 27,625 expressed lncRNAs, 2,744 of which were novel. Read More

    Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer.
    Cancer Res 2018 Jun 11. Epub 2018 Jun 11.
    Institute of Biosciences and Technology, Texas A&M University, Health Science Center
    The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. How it contributes to PCa progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here we report that FGFR1 tyrosine kinase reprograms the energy metabolism of PCa cells by regulating expression of lactate dehydrogenase (LDH) isozymes. Read More

    Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties.
    Cancer Res 2018 Jun 11. Epub 2018 Jun 11.
    Department of Pathology and Laboratory Medicine, University of Kansas Medical Center
    Drug development for front-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). Read More

    TET1-mediated hypomethylation activates oncogenic signaling in triple-negative breast cancer.
    Cancer Res 2018 Jun 11. Epub 2018 Jun 11.
    Temple University, School of Medicine
    Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Read More

    Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype.
    Cancer Res 2018 Jun 7. Epub 2018 Jun 7.
    Wise Laboratory of Genetic and Environmental Toxicology, University of Louisville
    A key hypothesis for how hexavalent chromium (Cr(VI)) causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can impact DNA repair and induce centrosome amplification, which can lead to structural and numerical CIN. However, no studies have considered whether these outcomes are transient or permanent. Read More

    Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis.
    Cancer Res 2018 Jun 7. Epub 2018 Jun 7.
    Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (originally named "Shanghai First People's Hospital")
    Exosomes are emerging as important mediators of the crosstalk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer (PC) remain largely unknown. Here we found that hypoxic exosomes derived from PC cells activate macrophages to the M2 phenotype in a HIF-1a or HIF-2a-dependent manner, which then facilitates the migration, invasion, and EMT of PC cells. Read More

    Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF-1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.
    Cancer Res 2018 Jun 7. Epub 2018 Jun 7.
    Departments of Pediatrics, Medicine, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine
    Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSCs), which are critical for tumor recurrence and metastasis. Here we demonstrate that hypoxia-inducible factor (HIF)-1-dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Read More

    Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence Following Radiation Therapy in Immunosuppressed Patients.
    Cancer Res 2018 Jun 7. Epub 2018 Jun 7.
    Department of Radiation Oncology, Stanford University School of Medicine
    Although radiation therapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy (BCT). The relationship between RT and local recurrence is unknown. Here we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. Read More

    The Canonical Wnt Pathway Drives Macropinocytosis in Cancer.
    Cancer Res 2018 Jun 5. Epub 2018 Jun 5.
    Cell Biology Program, Memorial Sloan Kettering Cancer Center
    Macropinocytosis has emerged as an important pathway of protein acquisition in cancer cells, particularly in tumors with activated Ras such as pancreatic and colon cancer. Macropinocytosis is also the route of entry of Bacillus Calmette-Guerin (BCG) and other microbial therapies of cancer. Despite this important role in tumor biology and therapy, the full mechanisms by which cancer cells can activate macropinocytosis remain incompletely defined. Read More

    Oncogenic properties of NEAT1 in prostate cancer cells depend on the CDC5L-AGRN transcriptional regulation circuit.
    Cancer Res 2018 Jun 5. Epub 2018 Jun 5.
    School of Life Sciences, Tsinghua University
    The long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been shown to regulate multiple cancer-related cellular activities including cell proliferation, apoptosis, and migration. In this study, we confirm that repression of NEAT1 induces DNA damage, disturbs the cell cycle, and arrests the proliferation of prostate cancer cells. By taking advantage of the prostate cancer tumor transcriptome profiles from The Cancer Genome Atlas (TCGA), our data-mining pipeline identified a series of transcription factors (TF) whose regulatory activities on target genes depended on the level of NEAT1. Read More

    Kras and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma.
    Cancer Res 2018 Jun 5. Epub 2018 Jun 5.
    Medicine, University of Rochester School of Medicine
    Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA with intermediates along this spectrum. Read More

    TCIApathfinder: an R client for The Cancer Imaging Archive REST API.
    Cancer Res 2018 Jun 5. Epub 2018 Jun 5.
    Biostatistis and Informatics, University of Colorado Boulder.
    The Cancer Imaging Archive (TCIA) hosts publicly available de-identified medical images of cancer from over 25 body sites and over 30,000 patients. Over 400 published studies have utilized freely available TCIA images. Images and metadata are available for download through a web interface or a REST API. Read More

    Targeting Rac and Cdc42 GTPases in Cancer.
    Cancer Res 2018 Jun 1;78(12):3101-3111. Epub 2018 Jun 1.
    Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.
    Rac and Cdc42 are small GTPases that have been linked to multiple human cancers and are implicated in epithelial to mesenchymal transition, cell-cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors that regulate their GDP/GTP exchange. Read More

    Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses.
    Cancer Res 2018 May 31. Epub 2018 May 31.
    Gastroenterology, Vanderbilt University Medical Center
    Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis and restricts M1 macrophage activation in gastrointestinal (GI) infections. However, the role of macrophage ODC in colonic epithelial-driven inflammation is unknown. Here we investigate cell-specific effects of ODC in colitis and colitis-associated carcinogenesis (CAC). Read More

    Helicase-driven activation of NFκB-COX2 mediates the immunosuppressive component of dsRNA-driven inflammation in the human tumor microenvironment.
    Cancer Res 2018 May 31. Epub 2018 May 31.
    Medicine, Roswell Park Comprehensive Cancer Center
    Presence of cytotoxic CD8+ T cells (CTL) in tumor microenvironments (TME) is critical for the effectiveness of immune therapies and patients' outcome, while regulatory T(reg) cells promote cancer progression. Immune adjuvants, including double-stranded (ds)RNAs which signal via Toll-like receptor-3 (TLR3) and helicase (RIG-I/MDA5) pathways, all induce intratumoral production of CTL-attractants, but also Treg attractants and suppressive factors, raising the question of whether induction of these opposing groups of immune mediators can be separated. Here we use human tumor explant cultures and cell culture models to show that the (ds) RNA Sendai Virus (SeV), poly-I:C, and rintatolimod (poly-I:C12U) all activate the TLR3 pathway involving TRAF3 and IRF-3, and induce IFNα, ISG-60, and CXCL10 to promote CTL chemotaxis to ex vivo-treated tumors. Read More

    SNHG6 acts as a genome-wide hypomethylation trigger via coupling of miR-1297-mediated S-adenosylmethionine-dependent positive feedback loops.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    General Surgery, Zhongnan Hospital of Wuhan University
    Aberrant genome-wide hypomethylation and long non-coding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. Read More

    The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Biotech Research and Innovation Centre (BRIC), University of Copenhagen
    Oligodendrogliomas (ODG) are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with ODG; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster orthologue of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Read More

    FGFR1-activated Translation of WNT Pathway Components with Structured 5' UTRs is Vulnerable to Inhibition of EIF4A-dependent Translation Initiation.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Department of Molecular and Cellular Biology, Baylor College of Medicine
    Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this crosstalk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multi-omics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. Read More

    Twist1 regulates Vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University.
    Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of Vimentin. How Twist1 regulates this expression remains unclear. Here we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of Vimentin in EMT. Read More

    Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Neurology, University of Virginia.
    Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. Read More

    Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Abramson Cancer Center, University of Pennsylvania
    Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T cell therapy. Mechanisms driving immunosuppression and poor T cell infiltration in PDA are incompletely understood. Here we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy (RT) and ICB with αCTLA-4 and αPD-1. Read More

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    Cancer Res 2018 May 29. Epub 2018 May 29.
    Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai.
    A key tool of cancer therapy has been targeted inhibition of oncogene addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here we use Drosophila to dissect response to targeted therapies. Read More

    Specific targeting of MTAP-deleted tumors with a combination of 2'-fluoroadenine and 5'-methylthioadenosine.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Cancer Biology, Fox Chase Cancer Center
    Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogs such as 6'-thioguanine (6TG) or 2'-fluoroadenine (2FA) with the MTAP substrate 5'-deoxy-5'-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analog toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogs into nucleotides. Read More

    Notch-induced myeloid reprogramming in spontaneous pancreatic ductal adenocarcinoma by dual genetic targeting.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Division of Solid Tumor Translational Oncology, DKFZ
    Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Read More

    Integrative modeling identifies key determinants of inhibitor sensitivity in breast cancer cell lines.
    Cancer Res 2018 May 29. Epub 2018 May 29.
    Division of Molecular Carcinogenesis, The Netherlands Cancer Institute
    Cancer cell lines differ greatly in their sensitivity to anticancer drugs as a result of different oncogenic drivers and drug resistance mechanisms operating in each cell line. Although many of these mechanisms have been discovered, it remains a challenge to understand how they interact to render an individual cell line sensitive or resistant to a particular drug. To better understand this variability, we profiled a panel of thirty breast cancer cell lines in the absence of drugs for their mutations, copy number aberrations, mRNA and protein expression and protein phosphorylation, and for response to seven different kinase inhibitors. Read More

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