tbuckley/cabot-search huggingface dataset:
Abstract 1539: Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer model
Authors: Mingfei Yan, Alexander Many, Hong Guan, Penelope M. Or, Andrew M. Chan
Journal: Cancer Research (2017)

Abstract PTEN (Phosphatase and tensin homolog) functions as a key negative regulator of PI3K-Akt pathway through its lipid phosphatase activity. Mutations or loss of PTEN is frequently observed in brain, breast, prostate and endometrial cancer. PTEN possesses a PDZ-binding domain (PDZ-BD) at the end of its carboxyl terminus. Functionally, PDZ-BD mediates PTEN’s interactions with other PDZ domain-containing proteins, including ZO-1, PSD-95, DLG, etc, which are involved in the formation of cell junctions, post-synaptic densities, and serves as scaffolding proteins for multiple signaling complexes. However, whether the PTEN PDZ-binding domain is required to suppress tumorigenesis still remains obscure. To study the role of PTEN PDZ-BD in breast epithelial tumorigenesis, a PTEN-ΔPDZ mice lacking this domain was generated. PTEN expression level and activity of PI3K-Akt pathway are not changed in the mammary epithelial cells, indicating that PDZ-BD is dispensable for PTEN stability and negative regulation of the PI3K-Akt pathway. Further, we crossed the PTEN-ΔPDZ mice with the MMTV-PyMT breast cancer model and observed increased total tumor burden as well as higher tendency of lung metastasis in PTEN-ΔPDZ mice. This data indicates that PTEN PDZ-BD is indeed important for tumor suppression during breast cancer progression. Previously, PTEN has been reported to govern the integrity of tight junctions and apical-basal polarity of epithelial cells, which requires PTEN’s interactions with other proteins through the PDZ-BD. However, through in vitro three-dimensional culture of primary mouse mammary epithelial cells, we failed to observe any disruption of either apical-basal polarity or tight junction. Meanwhile, we investigated the alteration of the transcriptome of breast cancer tissue in PTEN-ΔPDZ mice by performing RNA-sequencing. Several enriched signaling pathways were identified by Ingenuity Pathway Analysis (IPA), which seems to be mainly associated with cell skeleton signaling as well as signaling interaction between extracellular matrix and the cancer cell. A list of genes were validated by RT-PCR, and functional validation of these genes during the tumorigenesis in our animal model is to be carried out in the near future. This work was supported by a General Research Fund grant (#460713) from the Hong Kong University Grants Committee to AC. YM was supported by a Hong Kong PhD Fellowship (PF12-13584), and a Lo Kwee-Seong Biomedical Research Seed Fund to AC. Citation Format: Mingfei Yan, Alexander Many, Hong Guan, Penelope M. Or, Andrew M. Chan. Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1539. doi:10.1158/1538-7445.AM2017-1539
Abstract 3419: Uncovering the functional relevance of FBXW7 mutations in endometrial cancer
Authors: Mary Ellen Urick, Bo Hong, Meghan L. Rudd, Daphne W. Bell
Journal: Cancer Research (2017)

Abstract The goal of this study is to elucidate the functional consequences of FBXW7 mutations in the context of endometrial carcinoma (EC). EC is a heterogeneous disease, consisting of multiple histological subtypes associated with distinct clinical outcomes. Endometrioid endometrial cancer is the most commonly diagnosed subtype and is associated with an overall favorable prognosis. Less common but more clinically aggressive subtypes that contribute disproportionately to patient deaths include clear cell and serous ECs. We previously reported that FBXW7 is somatically mutated in 10% of endometrioid, 13% of clear cell and 29% of serous ECs. FBXW7 functions as a substrate-recognition protein within a SKP/CUL1/F-Box ubiquitin ligase complex, which targets numerous proteins for ubiquitin-mediated proteosomal degradation. Although FBXW7 is a known tumor suppressor, the functional consequences of these mutations have not yet been fully elucidated in the context of EC. As a means to this end, we utilized shRNA and Western blotting to identify proteins that are upregulated following FBXW7 depletion in ARK1 serous EC cells. Among proteins that were consistently upregulated were cyclin E1 and cMYC. We treated EC cells harboring endogenous FBXW7 mutations and those with wildtype FBXW7 with a proteasome inhibitor to confirm that EC cells regulate cyclin E1 and cMYC through proteasome degradation. Furthermore, we identified three EC cell lines that harbor endogenous mutations in FBXW7 and show that these cell lines exhibit delayed degradation of these substrates compared to EC cells expressing wildtype FBXW7. Finally, we generated expression constructs for wildtype FBXW7α and six recurrent mutants found in EC. We show that transient exogenous overexpression of five out of six recurrent FBXW7 mutant constructs in two different serous EC cell lines resulted in increased levels of phosphorylated cMYC and cyclin E1 compared to wildtype FBXW7α. These results suggest that not all recurrent FBXW7 mutations are functionally equivalent. Our findings begin to reveal the molecular consequences of FBXW7 mutations in EC and ongoing studies are aimed at elucidating additional functional consequences of these aberrations in the context of EC. Citation Format: Mary Ellen Urick, Bo Hong, Meghan L. Rudd, Daphne W. Bell. Uncovering the functional relevance of FBXW7 mutations in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3419. doi:10.1158/1538-7445.AM2017-3419
Abstract 3938: Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium
Authors: Yuen San Chan, Edwin-Wai Kin Yu, William Weimao Wang, Chi-Chun Fong, Timothy Tak-Chun Yip, Joseph Siu-Kie Au, Mengsu Yang
Journal: Cancer Research (2017)

Abstract Background Multiple subpopulations of cells with different phenotypes and genotypes coexist within malignant tumours. Different subpopulations seem to maintain themselves in an equilibrium position via stochastic interconversion. Such plasticity plays an important role in cancer progression, such as transition from epithelial states to mesenchymal state during metastasis, dedifferentiation of non-CSCs to CSCs and rapid transition to MDR cells during drug exposure. We attempt to explore this interconversion plasticity at both population and single cell levels to better understand the dynamics of phenotypic transition. Methods: We isolated CD90+ and CD90- cells from A549 lung adenocarcinoma cell line by flow cytometry and then characterized their phenotypic behaviors and interconversion dynamics at both population and single cells level. Single cells were cultured in 96 well plate for 13 days. Viable cells were then transferred into 6 well plate for further expansion until enough cells were collected for measurement of CD90 expression in flow cytometry. Results: A549 maintains a stable expression of CD90 (~50%) which is bimodal distributed. The sorted subpopulations eventually achieved a new equilibrium (CD90+ à 60% , CD90 - à 30%) and did not converge during the bulk cell interconversion. Individual single cell clones showed large variation of CD90 expression. The distribution of CD90 expression was significantly different between CD90+ and CD90- single cell clones, while both groups of clones achieved a similar average equilibrium as compared with the bulk cells. We noted two types of clones defined as transition clones and committed clones with differential interconversion capacities. The later one showed no sign of interconversion and was committed to the original CD90+/- expression level. Further experiments showed that the committed CD90+ cells were more mesenchymal with higher migration ability, while the committed CD90- cells were more epithelial and tumorigenic. Conclusions: Interconversion plasticity varied from cell to cell and the committed cells prohibited the return of sorted cell subpopulations returned back to the original equilibrium. Phenotypic studies of CD90+ and CD90- revealed that the interconversion between them was EMT related. Citation Format: Yuen San Chan, Edwin-Wai Kin Yu, William Weimao Wang, Chi-Chun Fong, Timothy Tak-Chun Yip, Joseph Siu-Kie Au, Mengsu Yang. Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2017-3938
Abstract 1878: PDZ-RhoGEF functions as a critical signaling effector for TROY
Authors: Zonghui Ding, Alison Roos, Jean Kloss, Harshil Dhruv, Marc Symons, Nhan L. Tran, Joseph C. Loftus
Journal: Cancer Research (2017)

Abstract Glioblastoma Multiforme (GBM) is the most common tumor of the CNS with a median survival of approximately 15 months. The highly aggressive invasion of malignant cells into the surrounding normal brain tissue renders complete surgical resection impossible, increases therapeutic resistance, and virtually assures tumor recurrence. We have previously demonstrated that TROY (TNFRSF19) has an important role in GBM invasion and resistance. TROY expression is correlated with glial tumor grade and inversely correlated with patient survival. Increased TROY expression stimulated cell migration/invasion in vitro and in vivo and confers resistance to both ionizing radiation- and temozolomide-induced apoptosis via activation of Akt and NF-κB. These data indicate that TROY stimulated migration/invasion is associated with signaling pathways that also increase survival and therapeutic resistance, however, the mechanistic basis of this signaling remains unclear. To investigate the mechanism by which TROY induces GBM cell invasion, we performed immunoprecipitation of the TROY receptor coupled with MALDI-TOF and MS/MS analysis and identified PDZ-RhoGEF as a binding partner for TROY. We validated the interaction of TROY with PDZ-RhoGEF by immunoprecipitation and western blotting, and demonstrated that PDZ-RhoGEF can exchange for both RhoA and RhoC in glioma cells and is implicated in GBM cell invasion, proliferation, and survival. In order to assess the specific role of PDZ-RhoGEF in TROY signaling, we examined the effects of PDZ-RhoGEF on TROY-mediated activation of NF-κB. While overexpression of TROY alone strongly stimulated NF-κB transcriptional activity in serum-free conditions, increased expression of PDZ-RhoGEF alone had no effect on NF-κB activity. Co-transfection of PDZ-RhoGEF with TROY synergistically promoted NF-κB activation. Mutation of the TRAF binding domain (TBD) in the cytoplasmic domain of TROY abolished its capacity to activate NF-κB, even in the presence of PDZ-RhoGEF, suggesting that the TBD is important for TROY induced NF-κB activation. Furthermore, knockdown of PDZ-RhoGEF by shRNA attenuated NF-κB activation in TROY expressing cells, blocked TROY mediated invasion of primary GBM xenograft cells and increased sensitivity to temozolomide. Collectively, these data indicate that PDZ-RhoGEF plays an important role in TROY signaling and provides insights into a potential node of vulnerability to limit GBM cell invasion and decrease therapeutic resistance. Citation Format: Zonghui Ding, Alison Roos, Jean Kloss, Harshil Dhruv, Marc Symons, Nhan L. Tran, Joseph C. Loftus. PDZ-RhoGEF functions as a critical signaling effector for TROY [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1878. doi:10.1158/1538-7445.AM2017-1878
Abstract 3815: The clinical impact of c-MET over-expression in advanced biliary tract cancers
Authors: Mi Hwa Heo, Seung Tae Kim, Young Suk Park, Joon Oh Park, Hansang Lee
Journal: Cancer Research (2017)

Abstract Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic BTC. Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results: The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathological variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), there was no significant difference in either RR or DCR (p=0.394 and 1.000, respectively). PFS for all 44 patients was 9.00 months (95%CI, 7.47-10.53 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95% CI, 12.8-19.2). There was a significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions: c-MET overexpression was detected in 34.1% of advanced BTC patients irrespective of tumor location. c-MET overexpression did not predict response to GC or survival. Further studies are needed to fully elucidate the value of c-MET overexpression as a novel biomarker in these patients. Citation Format: Mi Hwa Heo, Seung Tae Kim, Young Suk Park, Joon Oh Park, Hansang Lee. The clinical impact of c-MET over-expression in advanced biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3815. doi:10.1158/1538-7445.AM2017-3815
Abstract 2469: The B-cell lymphoma specific aptamer C10.36 binds a ribonucleoprotein complex on the cell surface of cancer cells
Authors: Sonal S. Tonapi, Janet E. Duncan, Matthew Rosenow, Melissa Richards, Teresa L. Tinder, Heather A. O'Neill, Mark R. Miglarese, David Spetzler, Michael Famulok, Günter Mayer
Journal: Cancer Research (2017)

Abstract Aptamers have recently gained prominence for their diagnostic and therapeutic potential. The DNA aptamer C10.36 forms a G-quadruplex and has been shown to bind the Ramos Burkitt’s lymphoma cell line. However, its binding partner on the cell surface remains unknown. Here we report on the identification of the molecular target of C10.36, which suggests its application in the therapy of B-cell lymphoma and leukaemia. Aptamer-affinity purification, followed by LC-MS/MS revealed unique proteins pulled down with C10.36 associated with Ramos cells but not Jurkat, a T-cell lymphocyte cell line. The majority of the identified target molecules were found to be associated within ribonucleoprotein complexes, of which the abundant and consistent ones belong to the nucleolin complex including nucleolin (NCL) itself and its interacting partners, i.e. nucleophosmin (NPM1), heterogeneous nuclear ribonucleoprotein (HNRNP) family members such as HNRNP C1C2 and U, rRNA 2'-O-methyltransferase fibrillarin (FBL), actin (ACTB), nucleolar RNA helicase 2 (DDX21), and proline- and glutamine-rich splicing factors (SFPQ). All proteins identified in the above ribonucleoprotein complex are aberrantly expressed on the surface of several disparate cancer cell types and have been shown to play an oncogenic role in cancer. Another G-rich anti-NCL aptamer, AS1411, has been shown to induce cell death in &amp;gt;100 cancer cell lines. Therefore, we tested the effect of C10.36 on viability of Ramos and other non-Hodgkin B-cell lymphoma (NHL) cancer cell lines. Our results indicate that C10.36 treatment causes specific cell death of certain lymphoma cell lines such as Ramos but not Jurkat cells. The present study identifies C10.36 as a novel anti-B cell lymphoma aptamer and underscores its potential for the development of a new targeted therapy to treat B-cell lymphomas. Citation Format: Sonal S. Tonapi, Janet E. Duncan, Matthew Rosenow, Melissa Richards, Teresa L. Tinder, Heather A. O'Neill, Mark R. Miglarese, David Spetzler, Michael Famulok, Günter Mayer. The B-cell lymphoma specific aptamer C10.36 binds a ribonucleoprotein complex on the cell surface of cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2469. doi:10.1158/1538-7445.AM2017-2469
Abstract 2168: Nucleic acid clamp-mediated recognition and transcriptional modulation of MYC oncogenes through the stabilization of G-quadruplexes
Authors: Taisen Hao, Tracy A. Brooks
Journal: Cancer Research (2017)

Abstract G-quadruplexes (G4s) tend to cluster around biologically important regions such as promoters of DNA, 5’-UTR of mRNA and telomeres. Modulating the stability of G4 as in these regulatory sequences is an emerging approach for cancer treatment. MYC proto-oncogene is overexpressed in over 80% of tumor types, contributing to deregulated cancer cell proliferation. Silencing MYC expression has been demonstrated to be an effective approach to inhibit tumor growth. Among all the silencing strategies, stabilizing MYC promoter G4 that serves as an on-off switch for the transcription of MYC has been explored by the targeting of small molecules. However, the binding specificity of small molecule retarded the drug development process. Exploring novel MYC G4-targeting strategies is necessary to potentiate the pharmacological specificity of MYC G4 modulation. Here, we adopted a nucleic acid clamp based approach to recognize and stabilize the physiologically predominant MYC G4. Previously, a clamp (clamp A) was been demonstrated to recognize the physiologically relevant MYC G4 with high specificity and to downregulate MYC promoter activity. In the current research, we modified and optimized this clamp to allow for flexibility with labeling and monitoring techniques. The original 18 Å polyethylene glycol phosphate linker connecting the 5’ and 3’ regions of clamp A were substituted with thymine bases of varying lengths; 5 thymines were found to be optimal. The binding specificity and MYC G4 recognizing ability of this optimized clamp A T5 were confirmed by EMSA and ECD; the G4 stabilizing ability of clamp A T5 was demonstrated by DMS footprinting. The cytotoxicity of clamp A T5 was examined by MTS assay on HEK-293 and MCF-7 cells. The intracellular localization of clamp A T5 is being determined microscopically with a 6-FAM-labeled clamp A T5 after being transfected into and incubated with HEK-293 and MCF-7 cells for 48 hr. Nuclear localization is being examined by co-staining with DAPI, and MYC promoter localization is being determined by clustering with a MYC FISH probe. The modification of the clamp is both cost-effective, and enables the detailed study of intracellular functions. This clamp has potential as both a diagnostic tool to inform the use of MYC G4-targeted small molecules, and as a nanotherapeutic. Citation Format: Taisen Hao, Tracy A. Brooks. Nucleic acid clamp-mediated recognition and transcriptional modulation of MYC oncogenes through the stabilization of G-quadruplexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2168. doi:10.1158/1538-7445.AM2017-2168
Abstract 3952: Rapid autopsy programs: A systematic review
Authors: Brian Li, Neesha Dhani, WeiYang Yu, Shawn Khan, Elysia Grose
Journal: Cancer Research (2017)

Abstract A Rapid Autopsy Program (RAP) is an advanced method of biospecimen procurement whereby autopsies are conducted within 2-6 hours postmortem in order to obtain substantial amounts of high-quality, fresh tissue in support of current and future research. Rapid autopsies were first introduced in the late 1980’s and are still a relatively novel approach, but growing in popularity as a viable alternative to traditional tissue sampling methods for cancer research. In oncology, primary tumour, metastatic, and normal tissue from uninvolved organ sites are sampled and can be subsequently snap frozen in liquid nitrogen or preserved in formalin-fixed paraffin-embedded blocks. Fresh tissue can also be distributed immediately to cancer researchers allowing for analyses incompatible with archival frozen or fixed tissue. Tissue degradation has been found to be minimized in different tissue types by decreasing the postmortem interval – the time between death and tissue preservation. Institutions capable of executing the collection and maintenance of such a repository of biospecimens are a monumental asset to clinicians and researchers who are interested in investigating tumour biology, metastatic disease, and treatment response. In addition to the clear scientific benefits of RAPs, these programs offer a unique opportunity for palliative cancer patients to donate their bodies to aid cancer research. This systematic review was conducted to examine the scope of impact of RAPs thus far on biomedical, translational, and clinical research in the field of oncology, in hopes to inform best practice for collection and use of biospecimen in oncology. Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, and Ovid MEDLINE will be searched with devised strategies and screened from inception until present. In addition, grey literature will be reviewed. Two independent reviewers will be responsible for study selection and data extraction. The results of the systematic review are pending. Citation Format: Brian Li, Neesha Dhani, WeiYang Yu, Shawn Khan, Elysia Grose. Rapid autopsy programs: A systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2017-3952