Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients.
Abstract Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell li...
Source: Neoplasia - October 21, 2020 Category: Cancer & Oncology Authors: Fan X, Li Y, Yi X, Chen G, Jin S, Dai Y, Cui B, Dai B, Lin H, Zhou D Tags: Neoplasia Source Type: research

Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation.
Abstract Fbw7 is a tumor suppressor that regulates the degradation of oncogenic substrates such as c-Jun, c-Myc, Notch1 intracellular domain (ICD), and cyclin E by functioning as the substrate recognition protein in the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex. Consequently, low expression or loss of FBXW7 in breast cancer has been hypothesized to result in the accumulation of oncogenic transcription factors that are master regulators of proliferation, apoptosis, and ultimately transformation. Despite this, the direct effect of Fbw7 loss on mammary gland morphology and tumorigenesis has not been examined. ...
Source: Neoplasia - October 21, 2020 Category: Cancer & Oncology Authors: Meyer AE, Furumo Q, Stelloh C, Minella AC, Rao S Tags: Neoplasia Source Type: research

Friends and foes: Our evolving understanding of the link between Fbxw7 and p53 in cancer.
PMID: 33070871 [PubMed - in process] (Source: Neoplasia)
Source: Neoplasia - October 21, 2020 Category: Cancer & Oncology Authors: Elizabeth Caldon C Tags: Neoplasia Source Type: research

Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription.
Abstract Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed ...
Source: Neoplasia - October 9, 2020 Category: Cancer & Oncology Authors: Fan Z, He L, Li M, Cao R, Deng M, Ping F, Liang X, He Y, Wu T, Tao X, Xu J, Cheng B, Xia J Tags: Neoplasia Source Type: research

Breast cancer cell debris diminishes therapeutic efficacy through heme oxygenase-1-mediated inactivation of M1-like tumor-associated macrophages.
In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs rest...
Source: Neoplasia - October 7, 2020 Category: Cancer & Oncology Authors: Kim SH, Saeidi S, Zhong X, Gwak SY, Muna IA, Park SA, Kim SH, Na HK, Joe Y, Chung HT, Kim KE, Han W, Surh YJ Tags: Neoplasia Source Type: research

A highly potent PROTAC androgen receptor (AR) degrader ARD-61 effectively inhibits AR-positive breast cancer cell growth in vitro and tumor growth in vivo.
In this study, we evaluated ARD-61 for its therapeutic potential and mechanism of action in breast cancer models in vitro and in vivo. ARD-61 potently and effectively induces AR degradation in AR+ breast cancer cell lines and is much more potent than enzalutamide in inhibition of cell growth and induction of cell cycle arrest and/or apoptosis. ARD-61 effectively induces complete AR degradation in xenograft tumor tissue and is more effective than enzalutamide in achieving tumor growth inhibition in the MDA-MB-453 xenograft model in mice. Our study provides strong preclinical rationale to develop AR degraders for the treatme...
Source: Neoplasia - September 18, 2020 Category: Cancer & Oncology Authors: Zhao L, Han X, Lu J, McEachern D, Wang S Tags: Neoplasia Source Type: research

Degrading AR-Dependent Cancers: Expanding the Role of PROTACs.
PMID: 32928364 [PubMed - in process] (Source: Neoplasia)
Source: Neoplasia - September 18, 2020 Category: Cancer & Oncology Authors: Michmerhuizen AR, Speers C Tags: Neoplasia Source Type: research

Targeting AGTR1/NF- κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma.
This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies. PMID: 32896760 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - September 3, 2020 Category: Cancer & Oncology Authors: Singh A, Srivastava N, Yadav A, Ateeq B Tags: Neoplasia Source Type: research

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis.
Abstract Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP i...
Source: Neoplasia - September 3, 2020 Category: Cancer & Oncology Authors: Frieling JS, Li T, Tauro M, Lynch CC Tags: Neoplasia Source Type: research

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion.
r M Abstract Aberrantly activated kinase signaling pathways drive invasion and dissemination in medulloblastoma (MB). A majority of tumor-promoting kinase signaling pathways feed into the mitogen-activated protein kinase (MAPK) extracellular regulated kinase (ERK1/2) pathway. The activation status of ERK1/2 during invasion of MB cells is not known and its implication in invasion control unclear. We established a synthetic kinase activation relocation sensor (SKARS) for the MAPK ERK1/2 pathway in MB cells for real-time measuring of drug response. We used 3D invasion assays and organotypic cerebellum slice culture t...
Source: Neoplasia - August 16, 2020 Category: Cancer & Oncology Authors: Schönholzer MT, Migliavacca J, Alvarez E, Santhana Kumar K, Neve A, Gries A, Ma M, Grotzer MA, Baumgartner M Tags: Neoplasia Source Type: research

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma.
In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response. PMID: 32818842 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - August 16, 2020 Category: Cancer & Oncology Authors: Koivisto CS, Parrish M, Bonala SB, Ngoi S, Torres A, Gallagher J, Sanchez-Hodge R, Zeinner V, Nahhas GJ, Liu B, Cohn DE, Backes FJ, Goodfellow PJ, Chamberlin HM, Leone G Tags: Neoplasia Source Type: research

I κB kinase-ε-mediated phosphorylation triggers IRF-1 degradation in breast cancer cells.
IκB kinase-ε-mediated phosphorylation triggers IRF-1 degradation in breast cancer cells. Neoplasia. 2020 Aug 09;22(10):459-469 Authors: Remoli AL, Sgarbanti M, Perrotti E, Acchioni M, Orsatti R, Acchioni C, Battistini A, Clarke R, Marsili G Abstract Interferon Regulatory Factors (IRFs) are key regulators of immunity, cell survival and apoptosis. IRF transcriptional activity and subcellular localization are tightly regulated by posttranscriptional modifications including phosphorylation. The IκB kinase family member IKK-ε is essential in regulating antiviral innate immunity ...
Source: Neoplasia - August 8, 2020 Category: Cancer & Oncology Authors: Remoli AL, Sgarbanti M, Perrotti E, Acchioni M, Orsatti R, Acchioni C, Battistini A, Clarke R, Marsili G Tags: Neoplasia Source Type: research

Deep tissue volumetric optoacoustic tracking of individual circulating tumor cells in an intracardially perfused mouse model.
sky D Abstract Widespread metastasis is the major cause of death from melanoma and other types of cancer. At present, the dynamic aspects of the metastatic cascade remain enigmatic. The feasibility to track circulating melanoma cells deep within living intact organisms can greatly impact our knowledge on tumor metastasis, but existing imaging approaches lack the sensitivity, spatio-temporal resolution or penetration depth to capture flowing tumor cells over large fields of view within optically-opaque biological tissues. Vast progress with the development of optoacoustic tomography technologies has recently enable...
Source: Neoplasia - July 8, 2020 Category: Cancer & Oncology Authors: Deán-Ben XL, Weidenfeld I, Degtyaruk O, Ntziachristos V, Stiel AC, Razansky D Tags: Neoplasia Source Type: research

Prognostic alternative mRNA splicing signatures and associated splicing factors in acute myeloid leukemia.
Abstract The dysregulation of alternative splicing (AS) has emerged as a mechanism of acute myeloid leukemia (AML). However, the prognostic impact of AS events remains under-explored in AML. Here we report the prognostic value of AS events and associated splicing factors based on three datasets of AML patients. We defined the landscape of AS events in AML and identified 7033 AS events associated with the survival of AML patients. Based on these events, we further developed a composite 15 AS event-based prognostic signature, which was independent of the cytogenetic risk stratification and patient age, and showed a ...
Source: Neoplasia - July 8, 2020 Category: Cancer & Oncology Authors: Jin P, Tan Y, Zhang W, Li J, Wang K Tags: Neoplasia Source Type: research

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor.
Abstract Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonst...
Source: Neoplasia - July 7, 2020 Category: Cancer & Oncology Authors: Xiong Y, Guo Y, Liu Y, Wang H, Gong W, Liu Y, Wang X, Gao Y, Yu F, Su D, Wang F, Zhu Y, Zhao Y, Wu Y, Qin Z, Sun X, Ren B, Jiang B, Jin W, Shen Z, Tang Z, Song X, Wang L, Liu X, Zhou C, Jiang B Tags: Neoplasia Source Type: research

Genomic characterization of Chinese ovarian clear cell carcinoma identifies driver genes by whole exome sequencing.
Abstract Little is known about the genetic alterations characteristic of ovarian clear cell carcinoma (OCCC). Our aim was to identify targetable genomic alterations in this type of cancer. Forty-two OCCC formalin-fixed, paraffin-embedded (FFPE) tissue samples were analyzed by whole-exome sequencing (WES), and 74 FFPE tissue samples underwent targeted sequencing (TS) to confirm the relevant driver mutations. Cell proliferation was assessed by cell counting kit-8 (CCK8) assays. In the 42 samples, ARID1A (64.3%) and PIK3CA (28.5%) were frequently mutated, as were PPP2R1A (11.9%), PTEN (7.1%) and KRAS (4.8%), which ha...
Source: Neoplasia - July 6, 2020 Category: Cancer & Oncology Authors: Yang Q, Zhang C, Ren Y, Yi H, Luo T, Xing F, Bai X, Cui L, Zhu L, Ouyang J, Jiang P, Fan W, Qiu J, Wang F, Xing X, Zhang Z, Zhang X, Zhang R Tags: Neoplasia Source Type: research

Ex vivo assessment of targeted therapies in a rare metastatic epithelial-myoepithelial carcinoma.
We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial-myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial-myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage...
Source: Neoplasia - July 5, 2020 Category: Cancer & Oncology Authors: Mäkelä R, Arjonen A, Suryo Rahmanto A, Härmä V, Lehtiö J, Kuopio T, Helleday T, Sangfelt O, Kononen J, Rantala JK Tags: Neoplasia Source Type: research

TROY signals through JAK1-STAT3 to promote glioblastoma cell migration and resistance.
Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a discouraging prognosis. Its aggressive and highly infiltrative nature renders the current standard treatment of maximal surgical resection, radiation, and chemotherapy relatively ineffective. Identifying the signaling pathways that regulate GBM migration/invasion and resistance is required to develop more effective therapeutic regimens to treat GBM. Expression of TROY, an orphan receptor of the TNF receptor superfamily, increases with glial tumor grade, inversely correlates with patient overall survival, stimulates...
Source: Neoplasia - July 2, 2020 Category: Cancer & Oncology Authors: Ding Z, Kloss JM, Tuncali S, Tran NL, Loftus JC Tags: Neoplasia Source Type: research

Dual inhibition of VEGF and PARP suppresses KRAS-mutant colorectal cancer.
Abstract The addition of bevacizumab to chemotherapy has prolonged overall and progression-free survival rates for metastatic colorectal cancer (mCRC). However, KRAS-mutant (KRAS-mut) CRC, lacking an ideal targeted agent, represents an inferior-response subgroup of patients. In the present study, we investigated a combination approach of bevacizumab + olaparib in KRAS-mut CRC in a preclinical setting. The combined therapy effectively prevented tumor growth in a KRAS-mut cancer cell-derived xenograft model, although this effect was not observed in vitro. Under bevacizumab treatment, we detected intratumor hypox...
Source: Neoplasia - July 2, 2020 Category: Cancer & Oncology Authors: Zhong L, Wang R, Wang Y, Peng S, Ma Y, Ding S, Yang H, Chen S, Luo X, Wang W Tags: Neoplasia Source Type: research

BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases.
Abstract The development of mutant BRAF inhibitors has improved the outcome for melanoma patients with BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes resulting in complete tumor regression, the majority of melanomas become resistant. To study resistance to BRAF inhibition, we developed a novel mouse model of melanoma using a tetracycline/doxycycline-regulated system that permits control of mutant BRAF expression. Treatment with doxycycline leads to loss of mutant BRAF expression and tumor regression, but tumors recur after a prolonged period of response to treatme...
Source: Neoplasia - July 2, 2020 Category: Cancer & Oncology Authors: Grigore F, Yang H, Hanson ND, VanBrocklin MW, Sarver AL, Robinson JP Tags: Neoplasia Source Type: research

TRIM11 promotes breast cancer cell proliferation by stabilizing estrogen receptor α.
TRIM11 promotes breast cancer cell proliferation by stabilizing estrogen receptor α. Neoplasia. 2020 Jun 26;22(9):343-351 Authors: Tang J, Luo Y, Tian Z, Liao X, Cui Q, Yang Q, Wu G Abstract Breast cancer is the most commonly diagnosed malignancy in female worldwide, over 70% of which are estrogen receptor α (ERα) positive. ERα has a crucial role in the initiation and progression of breast cancer and is an indicator of endocrine therapy, while endocrine resistance is an urgent problem in ER-positive breast cancer patients. In the present study, we identify a novel E3 ubiquitin ...
Source: Neoplasia - June 25, 2020 Category: Cancer & Oncology Authors: Tang J, Luo Y, Tian Z, Liao X, Cui Q, Yang Q, Wu G Tags: Neoplasia Source Type: research

Mathematical modeling of PDGF-driven glioma reveals the dynamics of immune cells infiltrating into tumors.
CONCLUSIONS: The chemoattractant gradient field produced by tumor cells may facilitate immune cells migration to the tumor cite. The chemoattractant production rate may be utilized to classify wtIDH1 and muIDH1 tumors. The dynamics of immune cells infiltrating into tumors is largely determined by tumor cell chemoattractant production rate and chemotactic coefficient. PMID: 32585427 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - June 21, 2020 Category: Cancer & Oncology Authors: Niu B, Zeng X, Phan TA, Szulzewsky F, Holte S, Holland EC, Tian JP Tags: Neoplasia Source Type: research

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.
Abstract OBJECTIVES: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines. MATERIALS AND METHODS: 176 surgically resected stage I-IV lun...
Source: Neoplasia - June 21, 2020 Category: Cancer & Oncology Authors: Talvitie EM, Vilhonen H, Kurki S, Karlsson A, Orte K, Almangush A, Mohamed H, Liljeroos L, Singh Y, Leivo I, Laitinen T, Kallajoki M, Taimen P Tags: Neoplasia Source Type: research

MDM2 amplification and fusion gene ss18-ssx in a poorly differentiated synovial sarcoma: A rare but puzzling conjunction.
Abstract The detection of specific alterations by genetic analyses has been included in the diagnostic criterions of the World Health Organization's classification of soft tissues tumors since 2013. The presence of a SS18 rearrangement is pathognomonic of synovial sarcoma (SS). MDM2 amplification is strongly correlated to well-differentiated or dedifferentiated liposarcoma (DDLPS) in the context of sarcoma. We identified one case of poorly differentiated sarcoma harboring both SS18-SSX2 fusion and MDM2 amplification. The review of the literature showed high discrepancies, concerning the incidence of MDM2 amplifica...
Source: Neoplasia - June 15, 2020 Category: Cancer & Oncology Authors: Di Mauro I, Mescam-Mancini L, Chetaille B, Lae M, Pierron G, Dadone-Montaudie B, Bazin A, Bouvier C, Michiels JF, Pedeutour F Tags: Neoplasia Source Type: research

Molecular mechanisms of Guadecitabine induced FGFR4 down regulation in alveolar rhabdomyosarcomas.
Abstract Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 ...
Source: Neoplasia - May 24, 2020 Category: Cancer & Oncology Authors: Darvishi E, Slemmons K, Wan Z, Mitra S, Hou X, Hugues Parmentier J, Eddie Loh YH, Helman LJ Tags: Neoplasia Source Type: research

Stemness regulation of the adrenal mixed corticomedullary tumorigenesis-a case-control study.
We reported a 32-year-old female, manifested with typical Cushing's syndrome and hypertension, to be diagnosed with right huge adrenal mixed corticomedullary tumor (8.8 cm). Right adrenalectomy was done to document the tumor intimately admixed with adrenal cortical adenoma and pheochromocytoma by biochemistry and immunohistochemistry. A case-control study was designed to explore the tumorigenesis of mixed corticomedullary tumor by whole exome sequencing. Expression of the stemness markers was controlled by a tissue array of 80 adrenal tumors. Overall, 1559 identical variants coexisted in parts of adrenal cortical adenoma...
Source: Neoplasia - May 17, 2020 Category: Cancer & Oncology Authors: Chiou HC, Jiang HJ, Yang SF, Kuo KK, Lin PC, Hsiao PJ Tags: Neoplasia Source Type: research

Corrigendum to "HMGA1 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration in in vitro models" [Neoplasia 18 (2016) 724-731].
Corrigendum to "HMGA1 expression in human hepatocellular carcinoma correlates with poor prognosis and promotes tumor growth and migration in in vitro models" [Neoplasia 18 (2016) 724-731]. Neoplasia. 2020 May 18;22(7):272-273 Authors: Andreozzi M, Quintavalle C, Benz D, Quagliata L, Matter M, Calabrese D, Tosti N, Ruiz C, Trapani F, Tornillo L, Fusco A, Heim MH, Ng CKY, Pallante P, Terracciano LM, Piscuoglio S PMID: 32438307 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - May 17, 2020 Category: Cancer & Oncology Authors: Andreozzi M, Quintavalle C, Benz D, Quagliata L, Matter M, Calabrese D, Tosti N, Ruiz C, Trapani F, Tornillo L, Fusco A, Heim MH, Ng CKY, Pallante P, Terracciano LM, Piscuoglio S Tags: Neoplasia Source Type: research

Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.
Abstract Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinoma...
Source: Neoplasia - May 7, 2020 Category: Cancer & Oncology Authors: Coleman DJ, Sampson DA, Sehrawat A, Kumaraswamy A, Sun D, Wang Y, Schwartzman J, Urrutia J, Lee AR, Coleman IM, Nelson PS, Dong X, Morrissey C, Corey E, Xia Z, Yates JA, Alumkal JJ Tags: Neoplasia Source Type: research

LIN28B promotes neuroblastoma metastasis and regulates PDZ binding kinase.
Abstract Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promot...
Source: Neoplasia - April 23, 2020 Category: Cancer & Oncology Authors: Chen D, Cox J, Annam J, Weingart M, Essien G, Rathi KS, Rokita JL, Khurana P, Cuya SM, Bosse KR, Pilgrim A, Li D, Shields C, Laur O, Maris JM, Schnepp RW Tags: Neoplasia Source Type: research

Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model.
In this study, we mined a cancer database and found that SAG is overexpressed in pancreatic cancer tissues and correlates with decreased patient survival. Whether Sag overexpression plays a causal role in pancreatic tumorigenesis is unknown. Here, we reported the generation of Sag transgenic mouse model alone (CS), or in combination with KrasG12D, driven by p48-Cre (KCS mice) for pancreatic specific Sag expression. Sag transgenic expression alone has no phenotypical abnormality, but in combination with KrasG12D promotes ADM (acinar-to-ductal metaplasia) conversion in vitro and mPanIN1 formation in vivo at the early stage, ...
Source: Neoplasia - April 23, 2020 Category: Cancer & Oncology Authors: Zhang Q, Wei D, Tan M, Li H, Morgan MA, Sun Y Tags: Neoplasia Source Type: research

MKL1/miR-5100/CAAP1 loop regulates autophagy and apoptosis in gastric cancer cells.
CONCLUSIONS: Our research reveals the mechanism by which the MKL1/miR-5100/CAAP1 loop regulates apoptosis and autophagy levels in gastric cancer cells, and miR-5100 is expected to become a new potential target for gastric cancer treatment. PMID: 32315812 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - April 17, 2020 Category: Cancer & Oncology Authors: Zhang HM, Li H, Wang GX, Wang J, Xiang Y, Huang Y, Shen C, Dai ZT, Li JP, Zhang TC, Liao XH Tags: Neoplasia Source Type: research

Corrigendum to "Prostaglandin F2 α-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity" [Neoplasia 21 (2019) 1073-1084].
Corrigendum to "Prostaglandin F2α-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity" [Neoplasia 21 (2019) 1073-1084]. Neoplasia. 2020 Apr 15;22(5):217-219 Authors: Jiménez-Segovia A, Mota A, Rojo-Sebastián A, Barrocal B, Rynne-Vidal A, García-Bermejo ML, Gómez-Bris R, Hawinkels LJAC, Sandoval P, Garcia-Escudero R, López-Cabrera M, Moreno-Bueno G, Fresno M, Stamatakis K PMID: 32304913 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - April 14, 2020 Category: Cancer & Oncology Authors: Jiménez-Segovia A, Mota A, Rojo-Sebastián A, Barrocal B, Rynne-Vidal A, García-Bermejo ML, Gómez-Bris R, Hawinkels LJAC, Sandoval P, Garcia-Escudero R, López-Cabrera M, Moreno-Bueno G, Fresno M, Stamatakis K Tags: Neoplasia Source Type: research

Liver fluke granulin promotes extracellular vesicle-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma.
Abstract Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, i...
Source: Neoplasia - March 30, 2020 Category: Cancer & Oncology Authors: Arunsan P, Chaidee A, Cochran CJ, Mann VH, Tanno T, Kumkhaek C, Smout MJ, Karinshak SE, Rodpai R, Sotillo J, Loukas A, Laha T, Brindley PJ, Ittiprasert W Tags: Neoplasia Source Type: research

Neddylation inactivation represses androgen receptor transcription and inhibits growth, survival and invasion of prostate cancer cells.
Abstract Androgen receptor (AR) and its constitutively active variants (AR-Vs) have been extensively implicated in the progression and recurrence of prostate cancer, making them attractive targets in the treatment of this disease. Whether and how neddylation modification regulates AR, and the therapeutic implications of this potential regulation, are relatively unexplored areas of investigation. Here we report that neddylation inactivation by the pharmacological inhibitor MLN4924 or Lenti-shRNA-based genetic knockdown of neddylation activating enzyme (NAE) selectively suppressed growth and survival of prostate can...
Source: Neoplasia - March 3, 2020 Category: Cancer & Oncology Authors: Zhou X, Han S, Wilder-Romans K, Sun GY, Zhu H, Liu X, Tan M, Wang G, Feng FY, Sun Y Tags: Neoplasia Source Type: research

Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes.
In this study, we report the establishment of an Alpha-Screen-based high throughput screen (HTS) assay for in vitro CUL5 neddylation, and screened a library of 17,000 compounds including FDA approved drugs, natural products and synthetic drug-like small-molecule compounds. Gossypol, a natural compound derived from cotton seed, was identified as an inhibitor of cullin neddylation. Biochemical studies showed that gossypol blocked neddylation of both CUL5 and CUL1 through direct binding to SAG-CUL5 or RBX1-CUL1 complex, and CUL5-H572 plays a key role for gossypol binding. On cellular level, gossypol inhibited cullin neddylati...
Source: Neoplasia - March 2, 2020 Category: Cancer & Oncology Authors: Yu Q, Hu Z, Shen Y, Jiang Y, Pan P, Hou T, Pan ZQ, Huang J, Sun Y Tags: Neoplasia Source Type: research

TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor- β signaling.
TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling. Neoplasia. 2020 Mar 03;22(4):163-178 Authors: Nyati S, Gregg BS, Xu J, Young G, Kimmel L, Nyati MK, Ray D, Speers C, Rehemtulla A Abstract BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient TGF-β signaling, through its role in stabilizing the TGFBR1 and TGFBR2 complex. Here we demonstrate that TGFBR2 phosphorylates BUB1 at Serine-318, which is conserved in primates. S318 phosphorylation abrogates the interaction of BUB1 with TGFBR1 and SMAD2. Using BUB1 truncation ...
Source: Neoplasia - March 2, 2020 Category: Cancer & Oncology Authors: Nyati S, Gregg BS, Xu J, Young G, Kimmel L, Nyati MK, Ray D, Speers C, Rehemtulla A Tags: Neoplasia Source Type: research

Erratum to "KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NF κB-Mediated CCL2 Production" [Neoplasia, Volume: 21, Issue:1, (2019) 52-60].
Erratum to "KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NFκB-Mediated CCL2 Production" [Neoplasia, Volume: 21, Issue:1, (2019) 52-60]. Neoplasia. 2020 Mar;22(3):e1 Authors: Chen R, Keoni C, Waker CA, Lober RM, Chen YH, Gutmann DH PMID: 32098655 [PubMed - in process] (Source: Neoplasia)
Source: Neoplasia - February 28, 2020 Category: Cancer & Oncology Authors: Chen R, Keoni C, Waker CA, Lober RM, Chen YH, Gutmann DH Tags: Neoplasia Source Type: research

AID assists DNMT1 to attenuate BCL6 expression through DNA methylation in diffuse large B-cell lymphoma cell lines.
Abstract The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6...
Source: Neoplasia - February 11, 2020 Category: Cancer & Oncology Authors: Jiao J, Lv Z, Zhang P, Wang Y, Yuan M, Yu X, Otieno Odhiambo W, Zheng M, Zhang H, Ma Y, Ji Y Tags: Neoplasia Source Type: research

Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers.
CONCLUSION: This is the first study to analyze the epigenome-wide 5hmC profiles among paired lung tumor and normal tissues. We observed global hypomethylation of 5hmC in lung cancers, and hypermethylated 5hmC enriched in CpG islands and gene upstream. We found that the genome-wide 5hmC levels do not correlate with the total methylation, and the GSA suggested different biological functions of 5hmC compared to 5modC. Overall, our results demonstrate the potential of 5hmC as a novel biomarker for lung cancer. PMID: 32062069 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - February 11, 2020 Category: Cancer & Oncology Authors: Wang Z, Du M, Yuan Q, Guo Y, Hutchinson JN, Su L, Zheng Y, Wang J, Mucci LA, Lin X, Hou L, Christiani DC Tags: Neoplasia Source Type: research

AGO2 phosphorylation by c-Src kinase promotes tumorigenesis.
Abstract Numerous studies have reported that c-Src is highly expressed with high tyrosine kinase activity in a variety of tumors. However, it remains unclear whether c-Src contributes to the miRNA pathway. Here, we report that c-Src can interact with and phosphorylate AGO2, a core component of RISC complex, at tyr 393, tyr 529 and tyr749. Mechanistically, it is confirmed that c-Src phosphorylation of AGO2 at tyr393 reduces its binding to DICER, thereby suppressing the maturation of long-loop pre-miR-192. However, the other two phosphorylation sites don't work on this function. Significantly, Ectopic expression of ...
Source: Neoplasia - January 21, 2020 Category: Cancer & Oncology Authors: Liu T, Zhang H, Fang J, Yang Z, Chen R, Wang Y, Zhao X, Ge S, Yu J, Huang J Tags: Neoplasia Source Type: research

Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer.
Abstract The serrated neoplasia pathway gives rise to a distinct subgroup of colorectal cancers distinguished by the presence of mutant BRAFV600E and the CpG Island Methylator Phenotype (CIMP). BRAF mutant CRC are commonly associated with microsatellite instability, which have an excellent clinical outcome. However, a proportion of BRAF mutant CRC retain microsatellite stability and have a dismal prognosis. The molecular drivers responsible for the development of this cancer subgroup are unknown. To address this, we established a murine model of BRAFV600E mutant microsatellite stable CRC and comprehensively invest...
Source: Neoplasia - January 10, 2020 Category: Cancer & Oncology Authors: Kane AM, Fennell LJ, Liu C, Borowsky J, McKeone DM, Bond CE, Kazakoff S, Patch AM, Koufariotis LT, Pearson J, Waddell N, Leggett BA, Whitehall VLJ Tags: Neoplasia Source Type: research

Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment.
Abstract Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effe...
Source: Neoplasia - January 9, 2020 Category: Cancer & Oncology Authors: Kregel S, Wang C, Han X, Xiao L, Fernandez-Salas E, Bawa P, McCollum BL, Wilder-Romans K, Apel IJ, Cao X, Speers C, Wang S, Chinnaiyan AM Tags: Neoplasia Source Type: research

Irreversible and sustained upregulation of endothelin axis during oncogene-associated pancreatic inflammation and cancer.
In conclusion, both chronic and acute pancreatic inflammation in the presence of oncogenic K-ras contribute to sustained upregulation of ET axis components in the ductal and stromal cells suggesting a potential role of ET axis in the initiation and progression of PDAC. PMID: 31923844 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - January 6, 2020 Category: Cancer & Oncology Authors: Gupta S, Prajapati A, Gulati M, Gautam SK, Kumar S, Dalal V, Talmon GA, Rachagani S, Jain M Tags: Neoplasia Source Type: research

Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.
Abstract While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly c...
Source: Neoplasia - December 29, 2019 Category: Cancer & Oncology Authors: Gupta P, Johns SC, Kim SY, El Ghazal R, Zuniga EI, Fuster MM Tags: Neoplasia Source Type: research

SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling.
Abstract Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and ...
Source: Neoplasia - December 25, 2019 Category: Cancer & Oncology Authors: Zhang A, Wang W, Chen Z, Pang D, Zhou X, Lu K, Hou J, Wang S, Gao C, Lv B, Yan Z, Chen Z, Zhu J, Wang L, Zhuang T, Li X Tags: Neoplasia Source Type: research

Long interspersed element-1 ribonucleoprotein particles protect telomeric ends in alternative lengthening of telomeres dependent cells.
n M Abstract Malignant cells ensure telomere maintenance by the alternative lengthening of telomeres (ALT) in the absence of telomerase activity (TA). The retrotransposons "long interspersed nuclear element-1" (LINE-1, L1) are expressed in malignant cells and are primarily known to contribute to complex karyotypes. Here we demonstrate that LINE-1 ribonucleoprotein particles (L1-RNPs) expression is significantly higher in ALT+- versus in TA+-human glioma. Analyzing a role of L1-RNP in ALT, we show that L1-RNPs bind to telomeric repeat containing RNA (TERRA), which is critical for telomere stabilization an...
Source: Neoplasia - December 13, 2019 Category: Cancer & Oncology Authors: Aschacher T, Wolf B, Aschacher O, Enzmann F, Laszlo V, Messner B, Türkcan A, Weis S, Spiegl-Kreinecker S, Holzmann K, Laufer G, Ehrlich M, Bergmann M Tags: Neoplasia Source Type: research

Deletion of tetraspanin CD151 alters the Wnt oncogene-induced mammary tumorigenesis: A cell type-linked function and signaling.
Abstract Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of cancer development and progression. Here we investigated the role of CD151 in breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated tumor growth and an increased number of Ki-67+ proliferative cells. Mechanistically, the CD151-deficient tumors were largely ER+, and exhibited ...
Source: Neoplasia - November 25, 2019 Category: Cancer & Oncology Authors: Li H, Li J, Han R, Deng X, Shi J, Huang H, Hamad N, McCaughley A, Liu J, Wang C, Chen K, Wei D, Qiang J, Thatcher S, Wu Y, Liu C, Thibault O, Wei X, Chen S, Qian H, Zhou BP, Xu P, Yang XH Tags: Neoplasia Source Type: research

Glutamine deprivation counteracts hypoxia-induced chemoresistance.
r T Abstract The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for...
Source: Neoplasia - November 21, 2019 Category: Cancer & Oncology Authors: Wappler J, Arts M, Röth A, Heeren RMA, Peter Neumann U, Olde Damink SW, Soons Z, Cramer T Tags: Neoplasia Source Type: research

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.
Abstract Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targe...
Source: Neoplasia - November 21, 2019 Category: Cancer & Oncology Authors: Sun J, Li G, Liu Y, Ma M, Song K, Li H, Zhu D, Tang X, Kong J, Yuan X Tags: Neoplasia Source Type: research

CDK5RAP3 is a co-factor for the oncogenic transcription factor STAT3.
nk DA Abstract The transcription factor STAT3 regulates genes governing critical cellular processes such as proliferation, survival, and self-renewal. While STAT3 transcriptional function is activated rapidly and transiently in response to physiologic signals, through a variety of mechanisms it can become constitutively activated in the pathogenesis of cancer. This leads to chronic expression of genes that underlie malignant cellular behavior. However, STAT3 is known to interact with other proteins, which may modulate its function. Understanding these interactions can provide insights into novel aspects of STAT3 f...
Source: Neoplasia - November 21, 2019 Category: Cancer & Oncology Authors: Egusquiaguirre SP, Liu S, Tošić I, Jiang K, Walker SR, Nicolais M, Saw TY, Xiang M, Bartel K, Nelson EA, Frank DA Tags: Neoplasia Source Type: research