bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3847: Tumor stem cell derived asymmetric dimethylarginine drives immune evasion via functional modulation of macrophages
Authors: Chen Yiling , Lowery AKaychia T. , Becerril Andres , Laventure Zaida T. , Ferguson Shareda , Chen Kuan-Hui Ethan 
Published: June 2022

Abstract
Macrophages are the most abundant tumor infiltrating immune cells and perform diverse immune functions including phagocytosis and incitation of T cells to mount an immune attack against tumors. However, the macrophage plasticity can lead to different outcomes of tumor progression and the amino acid, arginine, plays a central role in macrophage dichotomy. The exact role of arginine on the management of macrophage polarization is not completely understood. We have discovered that a methylated arginine metabolite, asymmetric dimethylarginine (ADMA), serves as an important regulator of macrophage functions. Upon stimulation by ADMA, macrophages have reduced survival and show a delayed tumor-phagocytic capacity. Additionally, ADMA blocks the Nitric Oxide Synthase (NOS) but not the Arginase activity in macrophages leading to a tendency of M2-like phenotype polarization. ADMA has minor effect on tumor cell proliferation but significantly drives the epithelial to mesenchymal transition. Tumor cells, particularly the tumor stem cells, are the major sources of ADMA. Production and secretion of ADMA by tumor (stem) cells profoundly increase when co-cultured with activated T cells or treated with T cell associated inflammatory cytokine, interferon-gamma (IFN-r). IFN-r initiates autophagy of tumor (stem) cells and inhibition of autophagy reduces the output of ADMA by tumor (stem) cells. Similarly, IFN-r enhances the proteasomal degradation and inhibition of the proteasomal pathway also reduces the ADMA production induced by IFN-r. In summary, our work shows that tumor (stem) cells may escape from immune surveillance (such as their exposure to activated T lymphocytes or to cytotoxic cytokine, IFN-r) through the secretion of ADMA generated via both autophagic and proteasomal pathways.
Citation Format: Yiling Chen, AKaychia T. Lowery, Andres Becerril, Zaida T. Laventure, Shareda Ferguson, Kuan-Hui Ethan Chen. Tumor stem cell derived asymmetric dimethylarginine drives immune evasion via functional modulation of macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3847.
Abstract 3850: Supermeres are functional extracellular nanoparticles replete with cancer biomarkers and therapeutic targets
Authors: Zhang Qin , Jeppesen Dennis K. , Higginbotham James N. , Glass Sarah E. , Franklin Jeffrey L. , Coffey Robert J. 
Published: June 2022

Abstract
Cancer-derived extracellular vesicles, including exosomes, and exomere nanoparticles, are under intense investigation for cargo that may serve as clinical biomarkers and therapeutic targets. Here, we report the discovery of a new extracellular nanoparticle, termed supemeres. Supermeres are morphologically different from exomeres as determined by fluid-phase atomic force microscopy and display distinct uptake both in vitro and in vivo. In colorectal cancer (CRC) cell-derived supermeres, TGFBI is the most abundant protein and is linked to CRC progression and survival. Supermeres are enriched with cargo involved in multiple cancers including glycolytic enzymes, AGO2, shed MET and GPC1, and miR-1246. The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab-resistance, and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential cancer-related circulating biomarkers and therapeutic targets.
Citation Format: Qin Zhang, Dennis K. Jeppesen, James N. Higginbotham, Sarah E. Glass, Jeffrey L. Franklin, Robert J. Coffey. Supermeres are functional extracellular nanoparticles replete with cancer biomarkers and therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3850.
Abstract 3853: Investigating PRL2/PTP4A2 as a new target for glioblastoma treatment
Authors: Chouleur Tiffanie , Derieppe Marie-Alix , Souleyreau Wilfried , Tremblay Michel L. , Bikfalvi Andreas 
Published: June 2022

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor. The standard treatment consists in tumor resection followed by chemo- and radio- therapy. However, tumor recurrence still remains inevitable, and the average lifespan of patients is only 15 months. Over the past decades, targeted therapies such as anti-angiogenic therapy, were proposed but failed to improve overall survival. In this context, the identification of new therapeutic targets is fundamental to implement current treatments. Protein Tyrosine Phosphatases (PTPs) are known to be involved in oncogenesis in several types of cancer, including GBM. Oncogenic properties of PRL2 has been demonstrated in different tumors (e.g. leukemia, breast, lung and nasopharyngeal cancer), but no evidence of PRL2 involvement in GBM has been reported so far. The aim of this project is to understand the role of PRL2 in GBM development, in order to evaluate the potential of PRL2 inhibition as a new therapeutic strategy. Analysis of TCGA (The Cancer Genome Atlas) dataset revealed that PRL2 was a poor prognostic factor in gliomas, and its expression correlated GBM aggressiveness. PTP4A2 expression also correlated with expression of genes involved in immune responses, reactive oxygen species, actin cytoskeleton and trafficking. Thus, we oriented our work towards these directions. To study PRL2 effects both in brain tumor cells and microenvironment, we used spheroids of patient-derived GBM cells, in which PTP4A2 expression was modulated. In vitro assays showed that migration, invasion and adhesion abilities were increased in PTP4A2-KO cells but cell proliferation was not affected. Next, in orthotopic xenografts experiments, PRL2 over-expression promoted tumor growth and reduced mouse survival rate. In addition, to overcome PRLs functional compensation and to use a clinically relevant strategy, we targeted all PRLs (PRL1, 2 and 3) activity with an inhibitory compound. Inhibiting all PRLs drastically reduced viability of GBM cells. Our project aims at discovering how PRL2 is involved in the progression and tumor microenvironment of GBM. Our results indicate that PRL2 promotes GBM growth in response to microenvironmental pressure and its inhibition improves mouse outcomes. However, the precise mechanisms of this regulation are still under investigation. Targeting PRLs and particularly PRL2 open avenue for therapeutic strategy in GBM treatment.
Citation Format: Tiffanie Chouleur, Marie-Alix Derieppe, Wilfried Souleyreau, Michel L. Tremblay, Andreas Bikfalvi. Investigating PRL2/PTP4A2 as a new target for glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3853.
Abstract 3858: Peristalsis-like mechanical stimuli in the intestinal milieu promotes colorectal cancer invasion through GABAergic signaling changes in an organ-on-chip platform
Authors: Strelez Carly , Chilakala Sujatha , Ghaffarian Kimya , Yoon Ah Young , Katz Jonathan , Mumenthaler Shannon M. 
Published: June 2022

Abstract
Mechanical forces in the tumor microenvironmental milieu are often understudied due to a lack of relevant preclinical model systems. Here we describe a microfluidic organ-on-chip platform that incorporates tissue-tissue interfaces and physical forces to aid in the examination of colorectal cancer (CRC) progression. A major advantage of this model is the ability to mimic peristalsis, a physiological process occurring in the gut. Live-cell imaging with a 3D printed organ-on-chip cradle was used to quantify the number of CRC cells that have invaded from the epithelial channel into the vascular channel over time. We determined that peristalsis-like motions in our organ-on-chip model enhanced the invasion capacity of CRC cells, mimicking intravasation. We subsequently examined the effluent media in stretched compared to non-stretched conditions using mass spectrometry based metabolomics and discovered an increase in the secretion of gamma-aminobutyric acid (GABA) by CRC cells, implicating peristalsis-mediated tumor cell invasion with neurotransmitter release. Inhibitors targeting the GABA-A receptor reversed the observed tumor cell invasion phenotype when cells were subjected to peristalsis-like motions. Interestingly, even in the absence of peristalsis, tumor cell invasion was promoted when GABA agonists were introduced into the organ-on-chip system. This work reveals important interactions between CRC cells and their microenvironment, and that disrupting GABAergic signaling might be an approach to prevent or delay cancer progression.
Citation Format: Carly Strelez, Sujatha Chilakala, Kimya Ghaffarian, Ah Young Yoon, Jonathan Katz, Shannon M. Mumenthaler. Peristalsis-like mechanical stimuli in the intestinal milieu promotes colorectal cancer invasion through GABAergic signaling changes in an organ-on-chip platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3858.
Abstract 3866: Spatial multi-omics analysis targeting protein and RNA biomarkers on a single FFPE tissue section using an integrated staining workflow
Authors: Chatterjee Gourab , Vezeau Grace E. , Lazova Milena D. , Sismour Michael , Manesse Mael 
Published: June 2022

Abstract
Biomarker detection approaches capable of rapid identification, quantification, and spatial mapping of many cellular sub-types of the tumor environment in FFPE tissue sections are becoming increasingly valuable for investigating the highly complex biology of tumors and their respective microenvironments. Multiplexed immunofluorescence (mIF) enables simultaneous identification of multiple protein targets within their spatial context in FFPE tissues, thereby facilitating more in-depth analysis including cellular phenotyping. In parallel, spatial transcriptomic analysis can provide additional insights into cellular function. Multi-omics analyses combining protein and nucleic acid biomarkers on a single tissue section can provide a deeper understanding of the complex cellular interactions in the context of the tumor. In this study, we demonstrate the versatility of Ultivue InSituPlex technology (ISP) through an integrated workflow for co-detection of protein and RNA on a single tissue section.
FFPE tumor tissue samples were processed for protein and/or RNA detection on a single slide with an integrated workflow using ISP. Briefly, slides were stained for both protein and RNA targets using a Leica Biosystems BOND RX autostainer. Post-staining, the slides were imaged on ZEISS Axioscan.Z1 in five different fluorescent channels and evaluated using IndicaLabs HALO analysis software. In parallel, control serial sections were stained to perform comparative analyses.
Here we report an efficient and streamlined integrated workflow for co-detection of protein and RNA on a single section, powered by ISP technology. The protein and RNA targets were detected both sequentially (over different imaging rounds) with increased multiplexing capabilities, as well as concurrently (in the same imaging round) for a higher throughput solution, thereby demonstrating the flexibility of the workflow. Comparative analyses between the different workflows confirmed minimal effect on staining performance of individual biomarkers (both protein and RNA).
The gentle treatment of FFPE tissue sections through ISP technology preserves tissue integrity, and morphology enabling efficient detection of protein and RNA targets on a single section. The integrated workflows presented here demonstrate compatibility of the individual steps in the assay towards co-detection of protein and RNA targets with efficient sensitivity in terms of staining performance for individual biomarkers.
Citation Format: Gourab Chatterjee, Grace E. Vezeau, Milena D. Lazova, Michael Sismour, Mael Manesse. Spatial multi-omics analysis targeting protein and RNA biomarkers on a single FFPE tissue section using an integrated staining workflow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3866.
Abstract 3896: Pimavanserin suppresses the growth of medulloblastoma by inhibiting Lyn/STAT3/MBSC signaling axis
Authors: Ramachandran Sharavan , Gaikwad Shreyas , Srivastava Sanjay K. 
Published: June 2022

Abstract
Medulloblastoma (MB) is one of the most frequently occurring malignant brain tumors in children, which accounts for 20% of all pediatric brain tumors and 40% of posterior fossa tumors. Despite advancements in the understanding of MB pathogenesis and identification of novel therapeutic targets, MB has emerged to be one of the most lethal pediatric diseases with peak incidences occurring in children aged between 5 and 7 years old. Numerous factors have been identified to hamper the management of several brain tumors including MB. However, the presence of medulloblastoma stem cells (MBSCs) and impermeability of drugs to cross the blood brain barrier (BBB) are identified as the major obstacles in MB management. MB is highly enriched with MBSCs, a subpopulation of MB cells that imparts therapy resistant, invasive and recurrent characteristics to MB. In our study, we evaluated the effects of Pimavanserin (PVT) in MB. Our results demonstrated that PVT treatment suppressed the proliferation of various MB cells by inducing apoptosis as shown by AnnexinV APC-PI assay. At molecular level, PVT inhibits Lyn/STAT3/MBSCs signaling axis. Additionally, chronic administration of PVT significantly suppressed the growth of subcutaneous and intracranial tumor xenografts without causing major side effects. Taken together, our study provides convincing evidence that PVT could serve as a novel treatment option for MB patients in the future. Ours is the first study to report to report the anti-cancer effects of PVT.
Citation Format: Sharavan Ramachandran, Shreyas Gaikwad, Sanjay K. Srivastava. Pimavanserin suppresses the growth of medulloblastoma by inhibiting Lyn/STAT3/MBSC signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3896.
Abstract 3906: Characterization of mTORC2 interactome reveals association with microtubules in glioblastoma and neuroblastoma cells
Authors: Pacharakullanon Narawit , Wongkongkathep Piriya , Tamanoi Fuyuhiko , Loo Joseph A. , Pisitkun Trairak , Chantaravisoot Naphat 
Published: June 2022

Abstract
The Mechanistic Target of Rapamycin Complex 2 (mTORC2) is a multiprotein complex representing one of the key players in the mTOR signaling pathway. This signal transduction is essential for the regulation of various cellular activities, including proper cell growth, proliferation, differentiation, survival, cell motility, and metabolism. Aberration of the mTOR cascade can be found in several types of disorders, including cancers and neurodegenerative diseases. It has been reported to correlate with acquired aggressive characteristics promoting metastasis, drug resistance, and recurrence in cancer cells and more progressive phenotypes in other diseased cells. More specifically, mTORC2 signaling promotes actin cytoskeleton reorganization, cell motility, cell survival, and has been recently reported to be responsible for DNA damage control. Unlike mTORC1 that has been more thoroughly studied, molecular mechanisms of mTORC2 are yet to be elaborated. Therefore, characterization of the mTORC2 signaling pathway will provide further information needed for better understandings of the biology of diseases. Previously, we have identified multiple cytoskeleton regulators, including actin-binding and microtubule-associated proteins as binding partners of mTORC2 in glioblastoma cells by affinity purification-mass spectrometry (AP-MS). In this work, we provided extensive characterization of mTORC2 interactome in both neuronal and non-neuronal cells focusing on microtubule-associated proteins. Interestingly, apart from many MAP proteins found in non-neuronal cells (glioblastoma), we identified Tau isoforms and their regulatory proteins such as Tau kinases from affinity-purified mTORC2 in neuroblastoma cells. The quantitative proteomic analyses of mTORC2-interacting proteins in various cellular conditions were performed to help determine the dynamics of the mTORC2-associated microtubule network. These novel protein-protein interactions acquired from this study suggested additional mTORC2 functions in different types of brain cells, which might also be beneficial to the understandings of neurodegenerative diseases in addition to cancers.
Citation Format: Narawit Pacharakullanon, Piriya Wongkongkathep, Fuyuhiko Tamanoi, Joseph A. Loo, Trairak Pisitkun, Naphat Chantaravisoot. Characterization of mTORC2 interactome reveals association with microtubules in glioblastoma and neuroblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3906.
Abstract 3913: Quantitative phosphoproteomic analysis of AXL signaling network in breast cancer
Authors: Wang Li , Pearson Nicole , Xiong Yuning , Renuse Santosh , Cheng Ran , Carter Jodi M. , Pandey Akhilesh , Wu Xinyan 
Published: June 2022

Abstract
Background: As a key receptor tyrosine kinase (RTK) regulating tumorigenesis, AXL is overexpressed in multiple different types of cancers. AXL can be activated by homodimerization after binding with its ligand, growth arrest specific 6 protein (Gas6) or by heterodimerization with other RTKs. AXL overexpression and/or activation have been reported to promote cancer cell proliferation, migration/invasion and to induce resistance to targeted therapy. However, the AXL downstream signaling network has not yet been fully elucidated.
Methods: We employed a CRISPR-CAS9-based knockout technology to create AXL inducible knockout cells in a human triple negative breast cancer (TNBC) cell line, HCC1395. In order to explore the downstream signaling events driven by AXL, we induced AXL knockout for 72 hours and used a 6-plex TMT-labeling-based quantitative proteomic approach to characterize the protein phosphorylation alterations induced by AXL knockout. IMAC and anti-phosphotyrosine antibody (pY1000)-based phosphopeptide enrichment methods were used to comprehensively quantify the phosphoproteome changes induced by AXL knockout.
Results: In this study, we identified 38,525 phospho serine/threonine sites and 1,427 phosphotyrosine sites. In response to AXL knockout, 1,581 phospho serine/threonine sites and 40 phosphotyrosine sites showed significant differences between AXL-KO and AXL-WT groups with &gt;1.5-fold change and p&lt;0.05 as the cutoff. Among them, 982 phosphoserine/threonine sites and 30 phosphotyrosine sites were decreased, while 599 phospho serine/threonine sites and 10 phosphotyrosine sites were increased in AXL-KO cells. Signaling pathway enrichment analysis revealed that suppressing AXL expression could inhibit multiple important cancer related signaling pathways, including cell cycle, focal adhesion, MAPK signaling pathway, p53 signaling pathway and mTOR signaling pathway.
Conclusion: Quantitative analysis of the phosphoproteome driven by AXL demonstrated that AXL plays a pivotal role in regulating canonical oncogenic signaling but also signaling pathways involved in RNA processing and DNA repair. Our data also suggest that targeting AXL could suppress these oncogenic signaling pathways and have therapeutic potential to improve clinical outcomes for patients with AXL overexpression.
Citation Format: Li Wang, Nicole Pearson, Yuning Xiong, Santosh Renuse, Ran Cheng, Jodi M. Carter, Akhilesh Pandey, Xinyan Wu. Quantitative phosphoproteomic analysis of AXL signaling network in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3913.
Abstract 394: Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance
Authors: Khamit-Kush Kofi Kyenku , Powell Joann B. , Handy Jeffrey A. , Bowen Nathan , Wu Daqing , Odero-Marah Valerie 
Published: June 2022

Abstract
The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is upregulated in high-grade prostate cancer (PCa). Previously published data from our lab shows that AhR protein is overexpressed and constitutively active in castration-resistant prostate cancer cells. Physiologically relevant leptin concentration is proportional to BMI and it is secreted by adipose cells to inhibit hunger under normal circumstances. Our preliminary results suggest that obesity-associated leptin concentrations desensitize PCa cells to cancer drugs however, the underlying mechanisms must be elucidated and may require sustained AhR signaling. In this study, we conducted an integrative bioinformatics analysis to explore the role of AHR and LEPR in PCa, which revealed AHR and LEPR mRNA expression positively correlates in prostate cancer (P&lt;0.05, Pearson: 0.68, R^2=0.46). The mRNA expression levels of AHR and LEPR in PCa tissue samples (i.e. solid tissue normal samples from individuals with cancer in TCGA, N=498) were analyzed using the cBioPortal and Xena online tools. We will further investigate if the decrease in drug response is seen in the presence of obesity-associated leptin concentrations. Further understanding of the potential interaction(s) between adipokines, AhR, and chemoresistance can promote improved treatments for patients with prostate cancer.
Citation Format: Kofi Kyenku Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan Bowen, Daqing Wu, Valerie Odero-Marah. Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 394.