bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3079: The antitumoral activity of metformin in glioblastoma stem cells is mediated by tmCLIC1 protein
Authors: Verduci Ivan , Cianci Francesca , Cannavale Gaetano , Castiglione Stefania , Ranucci Matteo , Mazzanti Michele 
Published: July 2021

Abstract
Glioblastoma (GB) is the deadliest brain tumor, representing a major clinical challenge in the field. Despite standard of care together with cutting-edge strategies, life expectancy stands invariantly poor. Tumor heterogeneity and its high-grade of invasiveness make it difficult to be surgically resected and recurrence is inevitable. There is scientific consensus that tumor relapse originates from progenitor/stem-like cells known as glioblastoma stem cells (GSCs) displaying properties of self-renewal and multi-lineage differentiation that contribute to tumor mass heterogeneity. Thus, GSCs represent the target of newly designed therapies. In recent years, it has been highlighted the anti-cancer properties of metformin, the first-line drug in Type-2 diabetes (T2D) treatment. Metformin assumption in T2D patients has been positively linked with a decrease in the risk of several cancer types and cancer-related mortality, including glioblastoma. Additionally, numerous studies demonstrated metformin's anticancer properties against GSCs. Despite metformin's mechanism of action on cancer cells has not been clarified yet, its effect has been proposed to target the oxidative phosphorylation (OXPHOS) pathway. Considering that GSCs have been reported to shuttle between glycolysis and OXPHOS energetic pathways, their metabolic plasticity should prevent the antiproliferative effect of metformin. However, metformin-treated GSCs show a phenotype superimposable to that caused by the blockage of the transmembrane form of the chloride intracellular channel 1 (tmCLIC1). tmCLIC1 involvement in the progression of GB has been assessed deeply in vitro as well as in vivo. In addition, its peculiar localization and enrichment on GSCs' membrane renders it a valuable pharmacological target for GB. The goal of the present work is to attest tmCLIC1 as the solely interactor with metformin in glioblastoma stem cells.
Ivan Verduci was supported by a AIRC fellowship for Italy.
Citation Format: Ivan Verduci, Francesca Cianci, Gaetano Cannavale, Stefania Castiglione, Matteo Ranucci, Michele Mazzanti. The antitumoral activity of metformin in glioblastoma stem cells is mediated by tmCLIC1 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3079.
Abstract 3080: ILEI regulates LIFR expression and CSC self-renewal
Authors: Streitfeld William S. , Dalton Annamarie C. , Howe Philip H. 
Published: July 2021

Abstract
Our lab has previously identified a mechanism of transforming growth factor beta (TGFβ)-mediated epithelial-to-mesenchymal transition (EMT) in normal murine mammary gland (NMuMG) cells. Reduced expression of heterogenous nuclear ribonucleoprotein E1 (hnRNP E1, hereafter “E1”) in NMuMG cells induces EMT, tumorigenesis, and metastasis. Our experimental data has revealed that increased expression of interleukin-like EMT inducer (ILEI) and of leukemia inhibitory factor receptor (LIFR) proteins occurs following E1 knockdown (E1KD). ILEI and LIFR have been shown to interact by coimmunoprecipitation/radiography experiments, and there is a correlation between ILEI expression and phosphorylation of the LIFR effector STAT3. ILEI is necessary to induce EMT in NMuMG cells, and spheroid formation capacity in non-adherent serum-depleted cell culture conditions is attenuated following either ILEI or LIFR knockdown. Loss of spheroid formation following ILEI knockdown is rescued by treatment with exogenous recombinant ILEI protein (rILEI); however, spheroid formation is not rescued by rILEI following LIFR knockdown. In immunocompromised mice, orthotopic grafts of NMuMG cells with E1KD (E1KD cells) with additional knockdown of either ILEI or LIFR display a decrease in tumor initiation, growth, and metastasis relative to control cells. These data suggest that ILEI-induced spheroid formation capacity involves LIFR, and that an ILEI/LIFR signaling axis promotes breast cancer stem cell (BCSC) phenotype. Characterization of the mechanisms that allow BCSCs to persist during chemotherapeutic interventions will advance our understanding of drug resistant and dormant breast cancer. The precise mechanisms involved in ILEI-mediated EMT and ILEI/LIFR-mediated BCSC induction are unknown. Semi-quantitative PCR data demonstrates that the increase in LIFR expression in E1KD cells is regulated at the transcriptional level. Additionally, E1KD cells with CRISPR-Cas9-mediated ILEI knockout (E1KD-ILEI-KO cells) show decreased luciferase signal relative to control cells following transfection of LIFR promoter DNA sequences placed upstream of a luciferase gene. Further, E1KD-ILEI-KO cells show attenuation of spheroid formation when compared to unaltered E1KD cells. Our data allow us to conclude that ILEI participates in the regulation of LIFR gene transcription, which plays a role in ILEI-induced maintenance of spheroid formation and self-renewal. Continued investigation will allow development of studies aimed at revealing the mechanisms involved in ILEI/LIFR axis-mediated disease progression in vivo.
Citation Format: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe. ILEI regulates LIFR expression and CSC self-renewal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3080.
Abstract 3081: Secretory human ribonuclease 1 functions as Eph receptor A4 ligand to promote breast tumor initiation
Authors: Wang Ying-Nai , Lee Heng-Huan , Yang Wen-Hao , Hortobagyi Gabriel N. , Yu Dihua , Hung Mien-Chie 
Published: July 2021

Abstract
The pancreatic human ribonuclease (hRNase) A superfamily is comprised of eight canonical hRNases, including hRNase 1, all of which can be detected in various body fluids, e.g., serum and plasma. Secretory hRNase 1 exerts its ribonucleolytic activity to function in extracellular RNA clearance. Moreover, hRNase 1 regulates hemostasis, inflammation, and innate immunity, indicating that hRNase 1 possesses multiple functions in addition to RNA clearance. Studies on hRNase 1 have been extensively investigated the biochemical properties and post-translational modifications, such as glycosylation. Nonetheless, the biological function of hRNase1 and whether it plays a role in cancer have not yet been completely defined. Recent studies indicated that hRNase 5 serves as a ligand for the receptor tyrosine kinase (RTK) epidermal growth factor receptor and plexin-B2 receptor in solid and hematopoietic cancers. Those findings reveal a role of the hRNase A superfamily in tumor progression and an unconventional ligand-receptor relationship between RNase and RTK families. Here, we demonstrate that hRNase 1, independently its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the RTK Eph receptor A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical ligand-receptor ephrin-EphA4 juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from the paired breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 to enhance breast cancer stemness suggests a potential treatment strategy for breast cancer by inactivating the hRNase 1-EphA4 axis.
Citation Format: Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Gabriel N. Hortobagyi, Dihua Yu, Mien-Chie Hung. Secretory human ribonuclease 1 functions as Eph receptor A4 ligand to promote breast tumor initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3081.
Abstract 3105: 4-Methylumbelliferone (4Mu) turns CD133+ lung cancer stem cells (CSCs) more susceptible to conventional chemotherapy
Authors: Bezazian Ana L. , Escribano Maria Amanda , Gutierrez Marco A. Diaz , Fusco Mariel , Roselló Paula , Menendez Juan Braga , Fiore Esteban J. , Fina Juan M. Bayo , Rizzo Manglio M. , Malvicini Mariana 
Published: July 2021

Abstract
Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide. Taxane-platin chemotherapy is widely used for NSCLC treatment; however, the majority of patients will ultimately progress or relapse. In the tumor microenvironment (TME) cancer cells co-exist with cellular and non-cellular components that drive tumor processes such as chemotherapy resistance. A small group of tumor cells called cancer stem cells (CSCs) that express some markers such as CD133, CD44 and ALHD1 have particularly different proliferative, differentiation and self-renewal potential. In fact, CD133+ NSCLC cells showed significantly higher abilities of self-renewal and drug resistance characteristics when compared to CD133- cells. It has been partly described how the TME component hyaluronan (HA) regulates CSCs function. We have previously demonstrated that 4-Methylumbelliferone (4Mu), a modulator of HA synthesis, reduces CSCs properties in hepatocarcinoma. Here, we observed that HA was present Lewis Lung Carcinoma (LLC) tumors from mice. We found HA+ LLC cells; thus cancer cells produced, at least in part, the HA observed in tumors. We also observed about 6.58 ± 0.83 % of CD133+ CSCs on in vitro cultured LLC cells. Isolated CD133+ cells showed higher expression of HA and CD44 in comparison with non-CSCs population (p&lt;0.05). Analysis of HA synthases (HAS), hyaluronidases (HYAL) and the CSCs transcription factors KLF4 and SOX2 expression from NSCLC patients using The Cancer Genome Atlas data showed that while HAS3 positively correlates with levels of KLF4 and SOX2, HYAL2 inversely correlates with SOX2 expression. Also, 4Mu treatment of whole, CD133+ or CD133- LLC cells showed an inhibitory concentration 50 (IC50) of 0.90mM, 0.60mM and 1.06mM respectively, while non tumor cells showed an IC50 of 4.22mM (p&lt;0.01). When CD133+ cells were treated with 4Mu plus pemetrexed or paclitaxel we observed a significant decrease in viability with an IC50 of 0.4nM pemetrexed (Pe) vs. 0.05nM Pe+4M, and 9.3nM paclitaxel (Pa) vs. 0.80nM Pa + 4Mu. (p&lt;0.05). Our results suggest that HA a principal ligand of CD44 is involved in CD133+ cells phenotype and their modulation by 4Mu could increases chemo sensibility of lung cancer stem cells.
Citation Format: Ana L. Bezazian, Maria Amanda Escribano, Marco A. Diaz Gutierrez, Mariel Fusco, Paula Roselló, Juan Braga Menendez, Esteban J. Fiore, Juan M. Bayo Fina, Manglio M. Rizzo, Mariana Malvicini. 4-Methylumbelliferone (4Mu) turns CD133+ lung cancer stem cells (CSCs) more susceptible to conventional chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3105.
Abstract 3115: Adora2a inhibition via caffeine as a novel therapeutic target for cisplatin-induced chemobrain
Authors: Oliveros Alfredo , Corujo-Ramirez Ana M. , Yoo Ki-Hyun , Tang Jason , Brogren Danielle , Rashid Mohammad A. , Liu Yuanhang , Jang Mi-Hyeon 
Published: July 2021

Abstract
Cisplatin chemotherapy, although efficacious in resolution of cancer, potentiates cognitive impairments (known as chemobrain) affecting approximately 14 million cancer survivors in the United States. Cisplatin is a frontline chemotherapy used to treat ovarian, testicular, breast and brain cancers. Despite the high prevalence of clinical reports of cognitive impairments during and following chemotherapy, there is little information on how learning/memory are detrimentally affected and no known cure. To elucidate the mechanisms by which chemobrain impairs cognition, we implemented a mouse model resembling intermittent cisplatin chemotherapy in humans. Our preliminary studies revealed that repeated intermittent cisplatin treatment detrimentally affects the structure of neuronal brain cells in the hippocampus, a brain region known for its ability to control learning/memory, emotional behaviors and motor function. Although the molecular pathways vulnerable to cisplatin in the brain remain elusive, gene sequencing from the hippocampus of mice administered cisplatin identified the adenosine A2A receptor (Adora2a) protein was concentrated in elevated quantities in this brain region. Importantly, the Adora2a receptor protein is known for its critical role in learning/memory and has been found to play a role in neurodegenerative conditions. To investigate Adora2a functionality in cisplatin-induced chemobrain, we assessed the efficacy of the non-selective Adora2a antagonist caffeine, in preventing cisplatin-induced cognitive dysfunction. Caffeine was selected as a therapeutic due to its safe pharmacological profile, its universal availability, and low cost. Our translational approach employing the non-selective Adora2a antagonist caffeine, protected against cisplatin-induced body weight deficits and motor dysfunction, both of which are common clinical symptoms of chemotherapy. Interestingly, relative to cisplatin alone, mice treated with caffeine in combination with cisplatin exhibited improved dendritic spine densities in the hippocampus, suggesting improved neuronal morphology by caffeine. Given that Adora2a antagonists are known to enhance anti-tumor activity while also showing neuroprotective promise in neurodegenerative conditions, inhibiting Adora2a during cancer treatment may have far-reaching synergistic effects on quality of life improvement for cancer survivors.
Citation Format: Alfredo Oliveros, Ana M. Corujo-Ramirez, Ki-Hyun Yoo, Jason Tang, Danielle Brogren, Mohammad A. Rashid, Yuanhang Liu, Mi-Hyeon Jang. Adora2a inhibition via caffeine as a novel therapeutic target for cisplatin-induced chemobrain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3115.
Abstract 3120: MMP-7 increases migration by decreasing intercellular cell junction complexes in prostate cancer microtumors formed by perlecan/HSPG2
Authors: Cruz Lissette A. , Tellman Tristen V. , Igoshin Oleg , Carson Daniel , Farach-Carson Mary (Cindy) 
Published: July 2021

Abstract
Background: Polarized epithelium is stabilized by lateral cell-cell interactions via cell adhesion molecules (CAMs) and by cell-matrix interactions with basement membrane including with perlecan/HSPG2 (pln). Prostate cancer (PCa) patients with bone metastases have circulating pln fragments, with inverse correlation between MMP-7 staining and loss of pln in cancer tissue. Cleavage of pln by MMP-7 increases cell-matrix interactions and dysregulates cell signaling, permitting migration. We earlier showed pln domain IV-3 (DmIV-3) drives cell-cell cohesion and, when digested with MMP-7, drives cell dyscohesion.
Methods: To evaluate the impact of MMP-7 and pln fragments on microtumor dyscohesion and cell migration, uniformly sized PCa microtumors were pre-formed in a microwell system. Pre-formed microtumors were transferred to Dm IV-3 or full length perlecan (FL pln) coated wells for 16-24 hrs. Microtumors were treated with MMP-7 alone or MMP-7 plus predigested Dm IV-3 fragments or MMP-7 plus FL pln fragments. For live cell imaging, tracking of migratory cells leaving microtumors was performed with Imaris software. Co-location of cell adhesion complex components was assessed with Imaris Spots.
Results: Pre-formed microtumors cultured with DmIV-3 cleaved by MMP-7 showed lower Pearson's correlation values at cell boundaries compared to microtumors treated with intact Dm IV-3. Line scan analysis revealed E-cadherin and F-actin fluorescent signals were enriched and co-aligned in microtumors treated with Dm IV-3; enrichment and co-alignment were reduced when DmIV-3 fragments and MMP-7 were present. Track number detected per cell cluster was highest in the presence of FL pln fragments plus MMP-7 along with a measurable change in distribution of track displacement lengths of cells toward high values.
Conclusion: Boundary reorganization promotes a migratory cell phenotype in microtumors treated with MMP-7 and DmIV-3 fragments. DmIV-3 fragments generated by MMP-7 cleavage can enhance cell dyscohesion by disrupting interactions between CAMs. Ongoing work will identify DmIV-3 fragment(s) positively associated with tumor dyscohesion that play key roles in secondary metastasis formation. Following patterns of dyscohesion of pre-formed microtumors provides a good model to study dynamic changes in intercellular junction components and quantitate cell migration patterns that foster circulating tumor cell formation and metastasis.
Citation Format: Lissette A. Cruz, Tristen V. Tellman, Oleg Igoshin, Daniel Carson, Mary (Cindy) Farach-Carson. MMP-7 increases migration by decreasing intercellular cell junction complexes in prostate cancer microtumors formed by perlecan/HSPG2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3120.
Abstract 3140: Tumor evolution selectively inactivates microRNA machinery for immune evasion
Authors: Zhao Haixin , Song Tian-yu , Long Min , Fan Hong-Jie , Liu Yang , Geng Chen-Lu , Xie Xiaoxiao , Huang Dawei , Peng Zhengang , Peng Bo , Cang Yong 
Published: July 2021

Abstract
Cancer arises after somatic mutations override cellular and immunological control of cell proliferation1. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to escape from immune surveillance during cancer evolution, but a targeted approach to uncover such mutations is lacking. We hypothesized that genetic heterogeneity intrinsic to cancer cells affects the cell fitness to T cell-mediated cytotoxicity. By deep sequencing of murine tumors grown under different conditions of immune editing, we identified 59 genetic mutations in clonal populations that were specifically enriched under host immune pressure. To differentiate driver from passenger mutations against immune selection, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting the corresponding genes. We identified ANKRD52 as required for PD-1-independent T cell-mediated cytotoxicity, which enhanced the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells. ANKRD52, in complex with PPP6C, dephosphorylates AGO26 and promoted microRNA (miRNA)-targeted silencing of suppressor of cytokine signaling 1 (SOCS1), and deletion of SOCS1 reinstalled the sensitivity of the mutant cells to T cell killing. Introduction of patient hotspot ANKRD52 mutations, or deletion of AGO2, DICER1 or XPO5 in cancer cells compromised the interferon-γ and T cell response. Remarkably, expression of the core miRNA biogenesis and targeting machinery strongly correlates with intratumoral T cell abundance across nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway is exploited by cancer cells for immune escape.
Citation Format: Haixin Zhao, Tian-yu Song, Min Long, Hong-Jie Fan, Yang Liu, Chen-Lu Geng, Xiaoxiao Xie, Dawei Huang, Zhengang Peng, Bo Peng, Yong Cang. Tumor evolution selectively inactivates microRNA machinery for immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3140.
Abstract 3141: Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer
Authors: Nath Aritro , Cosgrove Patrick , Copeland Benjamin , Mirsafian Hoda , Christie Elizabeth , Pflieger Lance , Majumdar Sumana , Cristea Mihaela , Han Ernest , Lee Stephen , Wang Edward , Fereday Sian , Traficante Nadia , Salgia Ravi , Werner Theresa , Cohen Adam , Moos Phillip , Chang Jeffrey , Bowtell David , Bild Andrea 
Published: July 2021

Abstract
The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells following chemotherapy is only partially understood. To uncover phenotypic changes associated with chemotherapy resistance, we profiled single-cell RNA-sequencing (scRNA-seq) transcriptomes of HGSOC tumors collected longitudinally during patient treatment. Analysis of scRNA-seq data from two independent patient cohorts revealed that HGSOC is driven by three core archetypal phenotypes, defined as oncogenic tasks that describe the majority of the transcriptome variation. A multi-task learning approach to identify the biological tasks of each archetype identified metabolism and proliferation, cellular defense response, and DNA repair signaling. The metabolism and proliferation archetype evolved during treatment and was enriched in cancer cells from patients that received multiple-lines of treatment and had elevated tumor burden indicated by CA-125 levels. The emergence of archetypes was not consistently associated with specific whole-genome driver mutations. However, archetypes were closely associated with subclonal populations at the single-cell level, indicating that subclones within a tumor often specialize in unique biological tasks. Our study reveals the core archetypes found in progressive HGSOC and shows consistent enrichment of subclones with the metabolism archetype as resistance is acquired to multiple lines of therapy.
Citation Format: Aritro Nath, Patrick Cosgrove, Benjamin Copeland, Hoda Mirsafian, Elizabeth Christie, Lance Pflieger, Sumana Majumdar, Mihaela Cristea, Ernest Han, Stephen Lee, Edward Wang, Sian Fereday, Nadia Traficante, Ravi Salgia, Theresa Werner, Adam Cohen, Phillip Moos, Jeffrey Chang, David Bowtell, Andrea Bild. Evolution of core archetypal phenotypes in progressive high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3141.