tbuckley/cabot-search huggingface dataset:
Abstract 3428: The role of methylthioadenosine phosphorylase in melanoma
Authors: Jennifer Jia-An Hsiao, Pedro Andreu-Perez, Miroslav Hejna, Lajos V. Kemény, Jun Song, David E. Fisher
Journal: Cancer Research (2020)

Abstract Methylthioadenosine phosphorylase (MTAP) is an enzyme that is expressed in virtually all normal tissues but lost in many cancers. MTAP deficiency can be due to either deletion of the MTAP gene or methylation of the MTAP promoter. In normal cells, MTAP catalyzes the conversion of methylthioadenosine (MTA), produced during polyamine biosynthesis, to adenine and 5-methylthioribose-1-phosphate, which is subsequently converted to methionine. Although recent genome wide association studies (GWAS) have associated the MTAP locus with melanoma risk, the molecular mechanisms linking MTAP loss to increased tumorigenesis are not yet fully understood. In this study, we hypothesized that loss of MTAP and the resulting accumulation of MTA would have an effect on microphthalmia transcription factor (MITF), the master regulator of melanocytes that has been shown to be an oncogene in melanoma. We present a novel signaling mechanism in which loss of MTAP and subsequent accumulation of MTA induces expression of MITF via inhibition of the phosphodiesterase PDE4D3 by MTA. Inhibition of PKA abolishes the induction of MITF, suggesting that the PKA pathway is hyperactivated when MTAP levels are low. We show that downregulation of MTAP expression leads to increased proliferation of melanoma cells. Using a melanoma xenograft mouse model, we observed that downregulation of MTAP expression leads to increased tumor growth in vivo. These data all point to MTAP as a tumor suppressor in melanoma, and indicate that MTAP loss is an alternative mechanism of dysregulating MITF, a known oncogene in melanoma. Citation Format: Jennifer Jia-An Hsiao, Pedro Andreu-Perez, Miroslav Hejna, Lajos V. Kemény, Jun Song, David E. Fisher. The role of methylthioadenosine phosphorylase in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3428.
Abstract 5918: The role of the cell-adhesion molecule Metadherin in inflammatory breast cancer progression
Authors: Gabriela Ortiz-Soto, Ivette J. Suárez-Arroyo, Michelle M. Martínez-Montemayor
Journal: Cancer Research (2020)

Abstract Inflammatory breast cancer (IBC) is the most lethal form of breast cancer where patients display a lower 5-year survival rate. The lethality of IBC originates from its nature of invading the vascular and lymphatic systems, absence of a tumor mass, and generation of tumor emboli. Currently, the accurate and early diagnosis and the development of effective targeted therapies remains a challenge. Thus, in an attempt to discover potential biomarkers, we characterized the IBC cell surface proteome. Plasma membrane proteins were identified via SILAC and MS quantitative proteomics using the IBC SUM-149 vs. MCF-10A a non-cancerous mammary epithelial cell line. SILAC results showed overexpression of Metadherin (MTDH) in IBC cells (&amp;gt;2.0 FCh) and was validated in IBC tissues and emboli. MTDH is a cell adhesion molecule overexpressed in many cancer types, including breast cancer. MTDH promotes cancer progression by modulating various signaling pathways including NF-kB, which is related to cell survival, proliferation, invasion and metastasis. Thus, the aim of this study is to assess the functional role of MTDH in IBC progression. To elucidate the mechanism of action of MTDH in colony formation and tumor spheroids we silenced MTDH (CRISPR or shRNA) SUM-149 and SUM-190 IBC cells. We assessed the expression of MTDH by immunoblotting and immunofluorescence where we observed reduced MDTH levels. The number of colonies formed in SUM-149 MTDH silenced cells was ~40% lower when compared to non-silenced cells. Tumor spheroids of SUM-149 and SUM-190 MTDH silenced cells were smaller than non-silenced cells. Additionally, MTDH silencing results in a decrease in the phosphorylation of the p65 subunit of NF-kB while no changes are observed in total protein abundance in SUM-149 cells. We can conclude from our preliminary results that MTDH serves as a potential IBC target for IBC progression. This work was supported by NIH NIGMS #GM111171 (MMM), SGRP 2017-00143 (MMM and GOS), NIMHD #MD007583 (MMM), GM103475 (UPR MMM), Title-V-PPOHA #P031M105050, Title-V-Cooperative #P031S130068 from the U.S. Dept. of Education and Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health #P20GM103475 (GOS). Citation Format: Gabriela Ortiz-Soto, Ivette J. Suárez-Arroyo, Michelle M. Martínez-Montemayor. The role of the cell-adhesion molecule Metadherin in inflammatory breast cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5918.
Abstract 5204: Targeting OGG1 arrest cancer cell proliferationby mitochondrial dysfunction and replication stress
Authors: Carlos Benitez-Buelga, Torkild Visnes, Kumar Sanjiv, Oliver Mortusewicz, Ulrika Warpman Berglund, Thomas Helleday
Journal: Cancer Research (2020)

Abstract Altered oncogene expression in cancer cells causes lost redox homeostasis resulting in oxidative DNA damage, e.g., 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER, and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstruct A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause lost mitochondrial function leading to S-phase damage, replication stress and lost proliferation or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g., PARP1, as potential targets for treatment of cancer. Citation Format: Carlos Benitez-Buelga, Torkild Visnes, Kumar Sanjiv, Oliver Mortusewicz, Ulrika Warpman Berglund, Thomas Helleday. Targeting OGG1 arrest cancer cell proliferationby mitochondrial dysfunction and replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5204.
Impact of protein glycosylation on lipoprotein metabolism and atherosclerosis
Authors: Angela Pirillo, Monika Svecla, Alberico Luigi Catapano, Adriaan G Holleboom, Giuseppe Danilo Norata
Journal: Cardiovascular Research (2020)

Abstract Protein glycosylation is a post-translational modification consisting in the enzymatic attachment of carbohydrate chains to specific residues of the protein sequence. Several types of glycosylation have been described, with N-glycosylation and O-glycosylation being the most common types impacting on crucial biological processes, such as protein synthesis, trafficking, localization, and function. Genetic defects in genes involved in protein glycosylation may result in altered production and activity of several proteins, with a broad range of clinical manifestations, including dyslipidaemia and atherosclerosis. A large number of apolipoproteins, lipoprotein receptors, and other proteins involved in lipoprotein metabolism are glycosylated, and alterations in their glycosylation profile are associated with changes in their expression and/or function. Rare genetic diseases and population genetics have provided additional information linking protein glycosylation to the regulation of lipoprotein metabolism.
Abstract 5953: Regulation of androgen receptor stability by nuclear export protein CRM1
Authors: Naiju Thomas, Rajendra Kumar, Deven Topiwala, Kavya Boyapati, Suthicha Kanacharoen, Michael Carducci, Samuel Denmeade, Sushant K. Kachhap
Journal: Cancer Research (2020)

Abstract Import of ligand-bound androgen receptor (AR) into the nucleus occurs with the help of nuclear importin. Past studies have identified a nuclear export signal (NES) in AR. CRM1 (also called XPO1 or Exportin1) is a well-studied exportin that exports proteins and RNA from the nucleus to the cytoplasm. GTP-bound active Ran, CRM1, and the cargo protein form a ternary complex that is exported through the nuclear pore complex. Previous experimental data indicate that RanGTP plays a vital role in Prostate cancer (PCa) progression. Our analyses further suggest that patients who have overexpression of CRM1 and/or Ran have significantly decreased survival. These results indicate that nucleocytoplasmic transport is essential for prostate cancer progression and inhibiting CRM1 could selectively inhibit cancer cell growth. We demonstrate that CRM1 does not affect the nuclear export of AR protein. However, quite surprisingly, we provide novel evidence that CRM1 binds to AR mRNA and is also required for AR protein stability. Inhibiting CRM1 using CRM1 inhibitor results in a dose-dependent rapid loss of AR and AR-V7 splice variants in PCa cells. This observation opens up an entirely new avenue to therapeutically regulate AR signaling using CRM1 inhibitors. Citation Format: Naiju Thomas, Rajendra Kumar, Deven Topiwala, Kavya Boyapati, Suthicha Kanacharoen, Michael Carducci, Samuel Denmeade, Sushant K. Kachhap. Regulation of androgen receptor stability by nuclear export protein CRM1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5953.
Abstract 304: Androgen deprivation induces epithelial to mesenchymal transition and neuroendocrine differentiation of prostate cancer via LIF-mediated phosphorylation of Smad2
Authors: Yen-Nien Liu, Shian-Ren Lin, Ntlotlang Mokgautsi, Hsiu-Lien Yeh, Jiaoti Huang
Journal: Cancer Research (2020)

Abstract The current therapies for prostate cancer, which can either be androgen-sensitive or androgen-insensitive ones, are based on AR-targeting approaches; however, there is no available treatment for neuroendocrine prostate cancer (NEPC). We previously identified the leukemia inhibitory factor (LIF), which is stimulated by androgen deprivation therapy (ADT). Here, we further elucidated the physiological relevance of LIF, whereby the high LIF output is associated with the activation of epithelial-to-mesenchymal transition (EMT), and neuroendocrine differentiation of prostate cancer cells through stimulation of transforming growth factor (TGF)-β signaling. We have elucidated the effect of LIF on inducing the EMT and NEPC progression through the stimulated TGF-β signaling via phosphorylation of Smad2. We also demonstrated that the inverse relationship between inhibition of AR signaling and induction of LIF-Smad2 signaling may predispose prostate cancer to metastasis. Importantly, an established activation in prostate cancer cells was shown between recombinant LIF protein and phosphorylation of Smad2, supporting the connection between LIF and p-Smad2. This was supported by the results obtained in high-LIF samples with elevated expression of p-Smad2 in tissues from high-grade prostate cancer. This study highlights the role of the important crosstalk between the LIF and TGF-β signaling pathways may exist and provide a new direction for investigating NEPC development. Citation Format: Yen-Nien Liu, Shian-Ren Lin, Ntlotlang Mokgautsi, Hsiu-Lien Yeh, Jiaoti Huang. Androgen deprivation induces epithelial to mesenchymal transition and neuroendocrine differentiation of prostate cancer via LIF-mediated phosphorylation of Smad2 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 304.
Abstract 3256: TIGIT humanized BALB/c mouse: A novel animal model for preclinical studies of human TIGIT antibodies
Authors: Cunxiang Ju, Mingkun Zhang, Xiaoliu Yang, Song Li, Hongyan Sun, Shuai Li, Jing Tang, Jing Zhao, Xiang Gao
Journal: Cancer Research (2020)

Abstract TIGIT is an immune-checkpoint receptor mainly expressed on activated and memory T cells, regulatory T cells (Tregs), and NK cells. Engaged with CD155 and CD112, TIGIT can transmit an inhibitory signal that negatively regulate the cell functionality. TIGIT blockade antibodies that release the inhibitory signals and direct potent tumor killing are currently under active development. However, animal models appropriate for preclinical evaluation of human TIGIT antibodies are still largely unmet. To solve this problem, we established a TIGIT humanized mouse model (hTIGIT) in which the extracellular domain of mTIGIT was replaced with human counterparts while the trans-membrane and cytoplasmic domain kept intact. These hTIGIT mice express similar level of chimeric TIGIT as compared to mTIGIT in wildtype mice. Surprisingly, the growth of subcutaneously engrafted CT26 tumor in BALB/c-hTIGIT mice, but not MC38 tumor in B6-hTIGIT mice, was strongly inhibited when treated with human TIGIT antibody (anti-TIGIT). TILs analysis on CT26 engrafted BALB/c-hTIGIT revealed significantly higher levels of intra-tumoral NK and Treg cells, and more interesting, Treg was remarkably deleted after anti-TIGIT intervention. Furthermore, Fc mutation that blocks ADCC effect completely abolished its therapeutic activity. These data suggested that tumor infiltrated Treg clearance by ADCC may contribute to the tumor inhibition observed in BALB/c-hTIGIT model. Taken together, BALB/c-hTIGIT mouse is a novel non-human animal model that can recapitulate the tumor environment and appropriate for direct preclinical efficacy study of human TIGIT antibodies. Citation Format: Cunxiang Ju, Mingkun Zhang, Xiaoliu Yang, Song Li, Hongyan Sun, Shuai Li, Jing Tang, Jing Zhao, Xiang Gao. TIGIT humanized BALB/c mouse: A novel animal model for preclinical studies of human TIGIT antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3256.
Abstract 2115: An atlas of transposable element derived alternative splicing in cancer
Authors: Evan A. Clayton, Lavanya Rishishwar, Tzu-Chuan Huang, Saurabh Gulati, Dongjo Ban, John F. McDonald, I. King Jordan
Journal: Cancer Research (2020)

Abstract Transposable element (TE) derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially utilized in normal versus cancer tissues. We analyzed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumor tissue pairs across 13 cancer types, resulting in the discovery of 4,820 TE-generated alternative splice events distributed among 723 cancer-associated genes. SINEs (Alu) and LINEs (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes - including MYH11, WHSC1, and CANT1 - were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans-splicing mediated by dispersed TE repeats. Citation Format: Evan A. Clayton, Lavanya Rishishwar, Tzu-Chuan Huang, Saurabh Gulati, Dongjo Ban, John F. McDonald, I. King Jordan. An atlas of transposable element derived alternative splicing in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2115.
Abstract 1520: RAB31 triggers oxaliplatin resistance in colorectal cancer via epithelial-mesenchymal transition
Authors: Chi-Long Chen, Yu-Chan Chang, Michael Hsiao
Journal: Cancer Research (2020)

Abstract Colorectal tumorigenesis during Epithelial-Mesenchymal transition (EMT) is associated with cancer metastasis and drug resistance. The small G-proteins family has been implicated in the regulation of cell cytoskeleton, cell movement, and vesicle transport. Small G-proteins family is divided into five main families. The Rab protein family is a member of the Ras superfamily of small G-proteins. We analyzed all probes of the Rab family members from microarray datasets and RNA-sequencing. We further calculated the EMT scores by using an algorithm. Our results showed that the RAB31 expression levels of the three probes are positively correlated with EMT score (Pearson rho=0.72, 0.71 and 0.68, respectively). Compared with other family members, RAB31 had most significantly value in colorectal cancer cell lines. We established several two-way model with cDNA and shRNAs of RAB31, respectively. Furthermore, we observed that the expression of epithelial type marker CDH1 was inhibited, and mesenchymal type markers SNAI1 and SNAI2 were upregulated in RAB31 overexpression models. Moreover, we found that the protein level of RAB31 was correlated with several clinicopathological parameters (N status, M status) and disease-free survival in tissue arrays through immunohistochemistry staining. According to The Cancer Genome Atlas Program (TCGA) and online meta-database, high RNA level of RAB31 was consistent in colorectal cancer (HR=1.38, n=466 and HR=1.29, n=482) and correlated with poor prognosis of patients. In addition, we identified that RAB31 may associated with IC50 of oxaliplatin and EGFR trafficking. We concluded that RAB31 regulates the sensitivity of oxaliplatin, an additional chemotherapy strategy and an independent prognostic factor for colorectal cancer. Citation Format: Chi-Long Chen, Yu-Chan Chang, Michael Hsiao. RAB31 triggers oxaliplatin resistance in colorectal cancer via epithelial-mesenchymal transition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1520.
Abstract 3497: The physical activity paradox in lung cancer: A systematic review and meta-analysis
Authors: Benny Rana, Liang Hu, Andrew Harper, Chao Cao, Cheryl Peters, Darren Brenner, Lin Yang
Journal: Cancer Research (2020)

Abstract Objective: To deliver a systematic review of the literature synthesizing data on the association of occupational physical activity with lung cancer risk in observational studies. Design: Systematic review with meta-analysis. Data Source: A literature search was performed in electronic databases of PubMed/Medline and Embase. Eligibility criteria for selecting studies: We screened for peer-reviewed articles from prospective cohort and case-control studies assessing the association of occupational physical activity with lung cancer risk. A sex-specific meta-analysis assessed the association of high (compared to low) level occupational physical activity with lung cancer risk, estimating the relative risk (RR) and odds ratio (OR) with a 95% confidence interval (CI). Results: The systematic search identified 2065 articles, among which, 13 journal articles met the inclusion criteria. The meta-analysis adjusted for age, status and/or intensity of smoking, with a pooled sample size of 623,741 participants (men: 263,530; women: 358,589). A random-effect model of four prospective and four case-control studies indicated that men who engage in high-level occupational physical activity had a 16% higher risk (OR 1.16, 95% CI 1.00 to 1.35) of lung cancer than those engaging in low-level occupational physical activity. There was no association observed among women (RR=1.05, 95% CI 0.81 to 1.36) based on three available studies (prospective cohort: n=2; case-control: n=1). Conclusions: Findings from the review suggest a higher risk of lung cancer among men reported high-level occupational physical activity. Further prospective studies incorporating rigorous measures of domain-specific physical activity and other occupational exposures are needed to elucidate this association. Citation Format: Benny Rana, Liang Hu, Andrew Harper, Chao Cao, Cheryl Peters, Darren Brenner, Lin Yang. The physical activity paradox in lung cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3497.