bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3159: CUX1 dosage-dependent regulation of hematopoietic stem and progenitor cells
Authors: Liu Weihan , Konecki Stephanie , Martinez Tanner , McNerney Megan 
Published: June 2022

Abstract
The mechanism by which stem and progenitor cells commit to proliferate, self-renew, or differentiate towards different lineages remains unclear. Understanding this process is essential to decipher both normal tissue development and aberrant differentiation associated with malignant transformation. CUX1 is a non-clustered HOX-family transcription factor that is recurrently mutated in hematopoietic and solid tumours and regulates cell fate in multiple developmental systems. We reported that CUX1 is required for normal hematopoietic homeostasis of both murine and human hematopoietic stem and progenitor cells (HSPCs). To date, the transcriptional role of CUX1 in HSPCs has been unclear, partly because of the complexity of the Cux1 locus. Namely, Cux1 shares exons with a distinct gene, Casp, which encodes a highly expressed golgi-associated protein. As most transcriptomic studies combine Casp and Cux1 transcripts, the nuances of Cux1 expression are concealed. To identify the transcriptional mechanism by which CUX1 regulates HSPC functions, we compared scRNA-seq data of Kit+lin- HSPCs from transgenic mice expressing inducible shRNAs targeting Cux1, Cux1mid and Cux1low, to control counterparts expressing an shRNA targeting renilla luciferase. We demonstrate that separating Cux1 from Casp transcripts provides more power to detect the influence of Cux1 in scRNA-seq data analysis. While cell numbers within most HSPC sub-populations are largely unchanged after five days of Cux1 knockdown, the transcriptomes within multiple clusters are disrupted. The effect size is greatest in Cux1low cells, compared to Cux1mid, consistent with dosage dependent roles of CUX1 in HSPCs. Across sub-populations, Cux1 levels correlated with gene signatures of “stemness,” and Cux1 knockdown disrupted this gene signature in the core hematopoietic stem cell (HSC) population. Concomitantly, low levels of Cux1 led to upregulation of cellular metabolism and G2/M cell cycle transition pathways in core HSCs, indicating that CUX1 regulates stem cell quiescence at the hematopoietic apex. We are currently integrating this data with epigenetic datasets to determine the mechanism by which CUX1 regulates critical hematopoietic transcriptional programs. Overall, understanding the regulatory function of CUX1 will provide insight into how HSCs commit to different fates and may ultimately lead to novel cancer therapeutic interventions.
Citation Format: Weihan Liu, Stephanie Konecki, Tanner Martinez, Megan McNerney. CUX1 dosage-dependent regulation of hematopoietic stem and progenitor 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 3159.
Abstract 3167: The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth
Authors: Kundu Somanath , Nandhu Mohan S. , Longo Sharon L. , Longo John A. , Rai Shawn , Chin Lawrence S. , Richardson Timothy E. , Viapiano Mariano S. 
Published: June 2022

Abstract
Proteins complexes that maintain the apico-basal polarity of epithelial cells and organize cell-signaling domains are necessary for normal tissue organization and therefore regarded as tumor suppressors. Accordingly, the scaffolding proteins that form the Scribble polarity complex (SCRIB, LLGL1, and DLG members) are usually downregulated in cancer, in particular in highly aggressive or invasive tumors. Because gliomas arise from non-epithelial precursors that are likely motile before transformation, the expression and functions of these scaffolding proteins in malignant brain tumors has remained almost entirely unexplored. Surprisingly, we have found that one member of the DLG family, DLG5, is highly upregulated in malignant gliomas compared to other solid tumors. Indeed, DLG5 was the predominant DLG member found in all molecular subtypes of glioblastoma (GBM). Knockdown of DLG5 reduced the viability, invasiveness, and self-renewal of GBM stem cells belonging to the proneural and mesenchymal molecular subtypes. As a result, intracranial tumors defficient in DLG5 were smaller and less proliferative than controls, resulting in extended animal survival. At the molecular level, DLG5 knockdown decreased the expression of stemness-related genes (SOX2, NANOG, POU5F1) but increased the expression of LLGL1, a component of the Scribble complex that is associated with neural precursor differentiation. These changes were accompanied by downregulation of Sonic Hedgehog (SHh) signaling, both in vitro and in vivo, which drives GBM cell stemness and proliferation. Moreover, DLG5-deficient GBM stem cells became insensitive to exogenous SHh and were unable to upregulate Gli1 or increase cell invasion in presence of added SHh, compared to control cells. We further confirmed that DLG5 downregulation increased the ubiquitination of Gli1-containing complexes as well as Gli1 proteasomal degradation, providing a suitable mechanism for the loss of SHh signaling and tumor stemness. These results describe for the first time the expression of a DLG family member in malignant gliomas and reveal a novel, polarity-independent, pro-tumoral function of DLG5, which differs from its proposed tumor-suppressor role in other solid tumors.
Citation Format: Somanath Kundu, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, Mariano S. Viapiano. The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth [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 3167.
Abstract 3185: Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms
Authors: Marini Kieren D. , Champion Emma C. , Cochrane Jennifer R. , Sweet-Cordero E. Alejandro 
Published: June 2022

Abstract
Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remain underexploited. Previously, we validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. From our genetically engineered mouse and our syngeneic modelling of LUAD we have observed that eCNTFR seems to work via two mechanisms, firstly in a tumor intrinsic fashion where it may modulate altered guanosine triphosphate loading, as we see differential effectiveness of eCNTFR-Fc, depending on the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate. Alternatively, eCNTFR also effects the tumor microenvironment and alters the composition of the tumor immune infiltrate, where using single cell genomics we see vast changes to the myeloid compartment, and alteration of the CAF populations, which we have previously shown to be the primary location of CLCF1 expression in mouse LUAD. To further enhance the efficacy of eCNTFR-Fc we have identified potential targets for combination therapy from both the autonomous and non-cell autonomous mechanisms of eCNTFR-Fc. We conclude that eCNTFR-Fc acts through two distinct mechanisms to be a highly effective treatment for Kras mutant LUAD, and combining eCNTER with targets, identified by a rational combination approach, could further enhance its therapeutic potential.
Citation Format: Kieren D. Marini, Emma C. Champion, Jennifer R. Cochrane, E. Alejandro Sweet-Cordero. Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms [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 3185.
Abstract 3204: Differential expression of angiogenesis-associated genes in smoker and non-smoker lung adenocarcinoma patients
Authors: Singh Shubhangi , Dasgupta Santanu , Turbat-Herrera Elba A. , Singh Seema , Singh Ajay P. 
Published: June 2022

Abstract
Tobacco smoke (TS) is one of the most prominent risk factors for lung and several other malignancies. Toxic chemicals present in TS induce DNA damage leading to carcinogenic mutations. Moreover, TS can also cause epigenetic and gene expression changes in tumor and other cells of the tumor microenvironment, especially through its addictive component nicotine. We and others have reported that nicotine promotes tumor angiogenesis via its direct impact on the endothelial cells or by altering the cancer cell secretome. In this study, we wanted to explore the association of smoking habits with the differential expression of angiogenesis-related genes in lung adenocarcinoma (LUAD) patients. Gene Set Enrichment Analysis (GSEA) identified a set of 48 angiogenesis-related genes that were surveyed for differential expression in smoker versus non-smoker patients in The Cancer Genomic Atlas (TCGA) database using an interactive web application, UALCAN. Gender and age of the LUAD patients were considered as confounding variables since patients of different age groups and gender can have biological and physiological differences, which could influence gene expression regardless of the smoking habits. We identified a total of fourteen differentially-expressed genes, of which four (HTATIP2, NCL, SPHK1, and VEGFA) were overexpressed and ten (AGGF1, AMOT, C1GALT1, ERAP1, NPR1, PML, RNH1, SHH, SPINL5, and TNFSF12) were downregulated in LUAD of smokers than those of non-smokers. Five of the differentially-expressed genes (HTATIP2, NCL NPR1, PML, and TNFSF12) exhibited significantly different transcript levels in males versus females and three (SPHK1, AGGF1, and SPINK5) showed varying pattern of expression in LUAD of different age group patients. Literature survey found prior published evidence for an association of two of the fourteen differentially expressed genes (NCL and NPR) with nicotine exposure. Together, our findings identify smoking-associated angiogenic gene signatures that could be potential effectors of nicotine signaling that promotes cancer angiogenesis and should be validated further by conducting laboratory investigations.
Citation Format: Shubhangi Singh, Santanu Dasgupta, Elba A. Turbat-Herrera, Seema Singh, Ajay P. Singh. Differential expression of angiogenesis-associated genes in smoker and non-smoker lung adenocarcinoma patients [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 3204.
Abstract 3207: Notch decoys as potential anti-angiogenic biotherapeutics
Authors: Sargis Timothy , Youn Seock-Won , Lee Hyun , Naiche L.A. , Kitajewski Jan 
Published: June 2022

Abstract
Notch signaling is activated by ligands Delta-like 4 (Dll4) and Jagged1 in the tumor microenvironment to promote tumor angiogenesis and perfusion. Notch activation is associated with poor outcomes in several cancers, particularly triple negative breast cancer (TNBC), and affects both tumor angiogenesis and metastasis. The development of therapeutics targeting angiogenesis, such as the Notch pathway, has again attracted attention. Previous approaches to globally inhibit the Notch pathway or block Dll4/Notch1 activation, such as γ-secretase inhibitors (GSI), have raised safety concerns due to gastrointestinal toxicity due to accumulation of secretory goblet cells in the intestine. Similarly, anti-Dll4 therapy resulted in pathological changes in the liver as well as severe vascular neoplasms when evaluated using preclinical animal models. Development of new approaches for targeting the Notch pathway remains a critical clinical problem currently unaddressed. Our lab has previously developed ligand-specific inhibitors of Notch signaling, called Notch decoys, which are comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain. These Notch decoys bind ligand non-productively and interfere with ligand function. Jagged-specific Notch1 decoys inhibit angiogenesis in vitro and significantly impair tumor growth, tumor angiogenesis, and perfusion without apparent toxicity in mouse models of TNBC. However, this previous work utilized Notch decoys produced via viral expression vectors, which preclude dosage control and limit clinical applicability. We have developed a new generation of Notch “mini” decoys that contain fewer EGF-like repeats. These mini decoys show improved secretion characteristics and can be purified as active proteins in clinically relevant quantities. Using a variety of binding assays, we observed that these Notch mini decoys demonstrate strong but distinct binding to Notch ligands Dll4 and Jagged1 and block Notch signaling when evaluated in cultured cells. Our newly generated Notch decoys can now be sufficiently purified for use in a dose-dependent manner to test the therapeutic role of Notch inhibition on tumor angiogenesis using preclinical animal models.
Citation Format: Timothy Sargis, Seock-Won Youn, Hyun Lee, L.A. Naiche, Jan Kitajewski. Notch decoys as potential anti-angiogenic biotherapeutics [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 3207.
Abstract 3236: CDK7 Expression is a biomarker of resistance to olaparib
Authors: Silberberg Gilad , Vishwakarma Bandana , Heverly Paul , Zipeto Marianna , DeOrnellis David , Ritchie Michael 
Published: June 2022

Abstract
The overall survival of patients diagnosed with Ovarian Cancer remains low. The current initial treatment regimen for patients with newly diagnosed advanced ovarian cancer includes the use of paclitaxel and carboplatin in combination with surgical cytoreduction. Remission is often achieved, but 80% of patients will have a recurrence within 3 years of remission. Recent treatment advances include the use of poly(ADP)-ribose polymerase (PARP) inhibitors for recurrent tumors with associated BRCA mutations. While maintenance treatment with PARP inhibitors results in remission for a significant number of patients, acquired resistance to therapy has been observed. In this study, we evaluated biomarkers associated with resistance to the PARP inhibitor Olaparib in a cohort of platinum pretreated Ovarian Cancer tumors. We identified Cyclin H and CDK7 expression, among others, as biomarkers associated with resistance to Olaparib. Further prospective analyses confirmed CDK7 expression as a biomarker of resistance to Olaparib in NSCLC.
Citation Format: Gilad Silberberg, Bandana Vishwakarma, Paul Heverly, Marianna Zipeto, David DeOrnellis, Michael Ritchie. CDK7 Expression is a biomarker of resistance to olaparib [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 3236.
Abstract 3252: Tumor treating fields suppression of ciliogenesis enhances temozolomide toxicity
Authors: Shi Ping , Tian Jia , Ulm Brittany , Mallinger Julianne , Khoshbouei Habibeh , Deleyrolle Loic , Sarkisian Matthew 
Published: June 2022

Abstract
Tumor Treating Fields (TTFields) are low intensity, alternating intermediate frequency (200kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer cells over normal cells, or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation, and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low and high grade patient glioma cell lines that TTFields ablated cilia within 24 hours. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons and multiciliated ependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Moreover, the inhibitory effects of TTFields and TMZ on tumor cell recurrence correlated with the relative timing of TMZ exposure to TTFields and ARL13B positive cilia. Finally, TTFields disrupted cilia in patient tumors treated ex vivo. Our findings suggest TTFields efficacy may depend on the degree of tumor ciliogenesis and relative timing of TMZ treatment.
Citation Format: Ping Shi, Jia Tian, Brittany Ulm, Julianne Mallinger, Habibeh Khoshbouei, Loic Deleyrolle, Matthew Sarkisian. Tumor treating fields suppression of ciliogenesis enhances temozolomide toxicity [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 3252.
Abstract 3265: Discovery of a first-in-class reversible DNMT1-selective inhibitor
Authors: Pappalardi Melissa B. 
Published: June 2022

Abstract
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A, and DNMT3B through irreversible covalent interactions. These agents induce significant toxicity to normal blood cells thus limiting their clinical doses. We report the discovery of a series of potent first-in-class DNMT1-selective inhibitors that compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA. These compounds induce robust loss of DNA methylation, transcriptional activation, and cancer cell growth inhibition in vitro leading to superior tumor regression and survival in mouse models of acute myeloid leukemia due to improved in vivo tolerability compared with decitabine.
Citation Format: Melissa B. Pappalardi. Discovery of a first-in-class reversible DNMT1-selective inhibitor [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 3265.
Abstract 3266: The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence
Authors: Smith Tunde M. , Chen Zhenbang , Stewart LaMonica V. 
Published: June 2022

Abstract
The members of the KDM5 family of lysine demethylases are best known for their ability to demethylate di- and trimethylated histone H3 at lysine 4 (H3K4me3). However, recent studies suggest at least three family members (KDM5A, KDM5B and KDM5C) promote prostate cancer growth and progression and may serve as effective therapeutic targets for this disease. Previous work from our laboratory has shown that 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), a compound that inhibits the enzymatic activity of multiple KDM5 isoforms, reduces the viability of castration-resistant prostate cancer cells. The goal of this study was to further characterize the anti-tumor effects of PBIT within human prostate cancers. Two models of human castration-resistant prostate cancer were used to define the effects of PBIT: the androgen receptor (AR) positive C4-2B cells and the PC3 cells, which express little to no AR. Our group initially demonstrated via quantitative RT-PCR analysis that PC3 and C4-2B cells express varying amounts of KDM5A, KDM5B, and KDM5C, the therapeutic targets of PBIT. Presto Blue assays were next performed to determine the extent to which PBIT alters cell proliferation. Micromolar concentrations of PBIT significantly reduced prostate cancer cell proliferation in a time- and concentration-dependent manner. Data from Cell Death ELISAs suggest that PBIT at a concentration of 10 μM did not significantly induce apoptosis within C4-2B or PC3 cells. However, PBIT does appear to induce cellular senescence within the PC3 cell line. The level of senescence associated beta-galactosidase staining was increased in PC3 cells following treatment with 10 μM PBIT. Furthermore, PBIT increased protein levels of a second senescence marker, lamin B1. Together, these data suggest that the induction of senescence contributes to the anti-proliferative effect of PBIT.
Citation Format: Tunde M. Smith, Zhenbang Chen, LaMonica V. Stewart. The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence [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 3266.